1,4-dihydropyridine and pyridine compounds as calcium channel blockers

ABSTRACT

The present invention is directed in part towards methods of modulating the function of calcium channels with pyridine- or 1,4-dihydropyridine-based compounds. In addition, the invention describes methods of preventing and treating protein kinase-related abnormal conditions in organisms with a compound identified by the invention. Furthermore, the invention pertains to pyridine- or 1,4-dihydropyridine-based compounds and pharmaceutical compositions comprising these compounds.

RELATED APPLICATIONS

The present application is a continuation of U.S. patent application Ser. No. 10/346,195, filed Jan. 14, 2003, by P. K. Pullela, et al., and entitled “1,4-DIHYDROPYRIDINE COMPOUNDS AS CALCIUM CHANNEL BLOCKERS,” which in turn claims priority to U.S. Provisional Application Ser. No. 60/350,331, filed Jan. 18, 2002, by P. K. Pullela, et al., and entitled “1,4-DIHYDROPYRIDINE COMPOUNDS AS CALCIUM CHANNEL BLOCKERS,” and U.S. Provisional Application Ser. No. 60/363,463, filed Mar. 11, 2002, by P. K. Pullela, et al., and entitled “1,4-DIHYDROPYRIDINE COMPOUNDS AS CALCIUM CHANNEL BLOCKERS,” all of which are incorporated by reference herein in their entirety, including any drawings.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to certain 1,4-dihydropyridine and pyridine compounds that can modulate the activity of calcium channels. These compounds can also be used for the treatment of diseases, such as cardiovascular disease or neurological disorders, that are associated with calcium channels.

2. Description of the Related Art

The pharmacological function and importance of calcium antagonists or calcium channel blockers, has been well documented. See, for example, R. A. Janis and D. J. Triggle “New developments in Ca ²⁺ channel antagonists” Journal of Medicinal Chemistry, 26, 775-785 (1983). Among the calcium antagonists, 4-aryl-1,4-dihydropyridine-3,5-dicarboxylic diesters (DHPs) of the nifedipine type have become almost indispensable for the treatment of cardiovascular diseases. For a review on Structure Activity Relations (SAR) see, S. Goldmann and J. Stoltefuss “1,4-Dihydropyridine: Effects of chirality and conformation on the calcium antagonist and calcium agonist activities” Angewandte Chemie International Edition (English) 30, 1559-1578 (1991). It was well documented that substitution on 4-phenyl ring is very crucial for pharmacological activity. Substituents at ortho or meta position improve the activity, whereas para substitution invariably decrease the activity. It was also published that bulkiness of ortho substituent, improves the calcium antagonist activity. B. Loev, M. M Goodman, K M. Snader, R. Tedeschi, E. Macko, “Hantzsch-Type Dihydropyridine hypotensive Agents”, Journal of Medicinal Chemistry 17, 956-965 (1974).

Voltage-gated calcium channels are large transmembrane proteins that regulate the intracellular concentration of calcium ions. They are classified into high (HVA) and low (LVA) voltage-activated channels according to the membrane potential at which they are activated. E. Carbone and H. D. Lux. “A low voltage activated, fully inactivating Ca channel in vertebrate sensory neuron” Nature, 310, 501-502, (1984): B. Nilius , P. Hess, J. B. Lansman and R. W. Tsien A novel type of cardiac calcium channel in ventricular cells. Nature, 316, 443-446. (1985).; M. C. Nowycky, A. P. Fox , R. W. Tsien. “Three types of neuronal calcium channels with different calcium agonist sensitivity” Nature 316, 440-443 (1985). LVA channels open and inactivate very fast, but deactivate about 10-100 times slower than HVA calcium channels. HVA channels require stronger membrane depolarizations to activate and can be divided further into N, P/Q,R and L-types based on their pharmacological properties. LVA channels can be detected in various tissues such as heart, brain, dorsal root ganglia and adrenal gland. The use of different search algorithms on mammalian expressed sequence tagged cDNAs or on similar sequences of the nematode Caenorhabditis elegans led to the identification of several genes, three of which encoded LVA calcium channels (T-type channels) and they have been named as α_(1G), α_(1H), α_(1I); see Review,. L. Lacinova, N. Klugbauer, F.Hofmann “Low voltage activated calcium channels: from genes to function” Gen. Physiol. Biophys., 19, 121-136, (2000). Of the above stated types of calcium channels, L-type channels received wide attention. Among the L-type channel blockers, Dihydropyridines (DHP) is the most widely studied. But, most of the DHPs are not selective against T-type channels and DHPs inhibiting the T-type channels is still sparse.

Voltage-gated calcium channels are important regulators of calcium influx in a number of cell types. Calcium entry through these channels activates a plethora of intracellular events, from the broad stimulation of gene expression, calcium-dependent second messenger cascades, and cell proliferation, to the specific release of neurotransmitter within the nervous system, and contraction in smooth and cardiac muscle (Tsien et al., 1988)(Wheeler et al., 1994); (Dunlap et al., 1995); (Tsien et al., 1991). A number of different types of calcium channels have been identified in native tissues and divided based on their biophysical profiles into low voltage activated (LVA) and high voltage activated (HVA) channels (Nowycky et al., 1985); (Tsien et al., 1991). LVA channels first activate at relatively hyperpolarized potentials and rapidly inactivate (Akaike et al., 1989); (Takahashi et al., 1991). By contrast, HVA channels require stronger membrane depolarizations to activate and can be divided further into N, P/Q-, R and L-types based on their pharmacological properties (for review, see (Stea et al., 1995); (Zamponi, 1997)). Molecular cloning has revealed that HVA channels are heteromultimers comprised of a pore forming α₁ subunit plus ancillary α₂-δ, β and possibly γ subunits (Pragnell et al., 1994); (Klugbauer et al., 1999); (Klugbauer et al., 2000); for review, see (Catterall, 2000), whereas LVA channels appear to contain only the a, subunit (Lacinova et al., 2000)). To date, ten different types of calcium channel al subunits have been identified and shown to encode the previously identified native calcium channel isoforms. Expression studies show that alternative splicing of α_(1A) generates both P- and Q-type Ca²⁺ channels (Bourinet et al., 1999), α_(1B) encodes N-type channels (Dubel et al., 1992)) α_(1C), α_(1D) and α_(1F) are L-type channels (Williams et al., 1992b); (Bech-Hansen et al., 1998), α_(1G), α_(1H) and α_(1I) form T-type channels (i.e., McRory et al., 2001) and α_(1E) may encode R-type channels (Soong et al., 1993); (Tottene et al., 1996), and α_(1S) encodes the skeletal muscle L-type channel isoform (Tanabe et al., 1987).

Dihydropyridine (DHP) antagonists of L-type calcium channels are widely used therapeutics in the treatment of hypertension, angina, arrhythmias, congestive heart failure, cardiomyopathy, atheriosclerosis, and cerebral and peripheral vascular disorders (Janis and Triggle, 1990) CRC Press, Cleveland. DHPs having a tendency to selectively block and enhance native L-type calcium channel activity. B. P.(Bean, 1984).; B. .Z. (Peterson and Catterall, 1995). In addition to L-type channel activity, some of the DHPs are sensitive to T-type channel activity. (N. Akaike, H. Kanaide, T, Kuga, M, Nakamura, J. Sadoshima and Tomoike “Low Voltage Activated Calcium Current in rat Aorta Smooth Muscle Cells In Primary Culture” J Physiol. 416, 141-160, (1989).

SUMMARY OF THE INVENTION

Disclosed are compounds of Formulae I and II

or a pharmaceutically acceptable salt, amide, ester, or prodrug thereof, where

-   -   a) R₁ is an straight-chain, branched, or cyclic alkyl group         having greater than eight carbon atoms;     -   b) R₂-R₉ are each independently selected from the group         consisting of hydrogen, halogen, perhaloalkyl, nitro, amino, a         diazo salt, optionally substituted lower alkyl, optionally         substituted lower alkylene, optionally substituted lower alkoxy,         optionally substituted lower alkoxyalkyl, optionally substituted         lower alkoxyalkoxy, optionally substituted lower mercaptyl,         optionally substituted lower mercaptoalkyl, optionally         substituted lower mercaptomercaptyl, —C(O)OH, —OC(O)H, —C(O)OR,         —OC(O)R, —C(S)OR, —OC(S)R, —C(O)SR, —SC(O)R, —C(S)SR, —SC(S)R,         C-amido, N-amido, and optionally substituted five- or         six-membered heteroaryl ring or optionally substituted         six-membered aryl or heteroaryl ring,         -   where the lower alkyl and the lower alkylene moieties are             each independently and optionally substituted with one or             more substituents selected from the group consisting of             halogen, perhaloalkyl, nitro, amino, hydroxy, alkoxy,             sulfhydryl, thioether, cyano, amido, ester, and

-   -   -   -   where A is selected from the group consisting of oxygen,                 sulfur, and —NH and R₁₂ is selected for the group                 consisting of hydrogen, hydroxy, alkoxy, haloalkoxy,                 halogen, haloalkyl, perhaloalkyl, nitro, amino, and a                 diazo salt, and n is between 0-4; and

        -   where the ring moieties are each independently and             optionally substituted with one or more substituents             selected from the group consisting of lower alkyl, lower             alkylene,

    -   c) R₁₀ and R₁₁ in the compound of Formula I are each         independently selected from the group consisting of hydrogen and         lower alkyl.

Also disclosed is a method of modulating the activity of a calcium channel in a cell comprising the step of contacting the cell with a compound as described above.

In addition, disclosed is a method of treating a disease associated with a cellular calcium channel comprising identifying a subject in need of such treatment; and administering to the subject a therapeutically effective amount of a compound as described above.

Furthermore, pharmaceutical compositions are disclosed comprising a compound as described above, and a physiologically acceptable carrier, diluent, or excipient, or a combination thereof.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

Here, we report a novel series of DHP derivatives (dialkyl1,4-dihydro-4-(2′-alkoxy-6′-pentadecylphenyl)-2,6-dimethyl-3,5-pyridine dicarboxylates). These compounds will exhibit activity as calcium channel antagonists, and can be used for the various purposes for which these types of compounds are known.

I. Compounds of the Invention

Thus, an aspect of the present invention relates to a compound of Formula I or Formula II

or a pharmaceutically acceptable salt, amide, ester, or prodrug thereof, where

-   -   a) R₁ is an straight-chain, branched, or cyclic alkyl group         having greater than eight carbon atoms;     -   b) R₂-R₉ are each independently selected from the group         consisting of hydrogen, halogen, perhaloalkyl, nitro, amino, a         diazo salt, optionally substituted lower alkyl, optionally         substituted lower alkylene, optionally substituted lower alkoxy,         optionally substituted lower alkoxyalkyl, optionally substituted         lower alkoxyalkoxy, optionally substituted lower mercaptyl,         optionally substituted lower mercaptoalkyl, optionally         substituted lower mercaptomercaptyl, —C(O)OH, —OC(O)H, —C(O)OR,         —OC(O)R, —C(S)OR, —OC(S)R, —C(O)SR, —SC(O)R, —C(S)SR, —SC(S)R,         C-amido, N-amido, and optionally substituted five- or         six-membered heteroaryl ring or optionally substituted         six-membered aryl or heteroaryl ring,         -   where the lower alkyl and the lower alkylene moieties are             each independently and optionally substituted with one or             more substituents selected from the group consisting of             halogen, perhaloalkyl, nitro, amino, hydroxy, alkoxy,             sulfhydryl, thioether, cyano, amido, ester, and

-   -   -   -   where A is selected from the group consisting of oxygen,                 sulfur, and —NH and R₁₂ is selected for the group                 consisting of hydrogen, hydroxy, alkoxy, haloalkoxy,                 halogen, haloalkyl, perhaloalkyl, nitro, amino, and a                 diazo salt, and n is between 0-4; and

        -   where the ring moieties are each independently and             optionally substituted with one or more substituents             selected from the group consisting of lower alkyl, lower             alkylene,

    -   c) R₁₀ and R₁₁ in the compound of Formula I are each         independently selected from the group consisting of hydrogen and         lower alkyl.

In another aspect, the invention relates to a compound of Formula I or Formula II

or a pharmaceutically acceptable salt, amide, ester, or prodrug thereof, where

-   -   a) R₁ is an straight-chain, branched, or cyclic alkyl group         having greater than eight carbon atoms;     -   b) R₂-R₉ are each independently selected from the group         consisting of hydrogen, halogen, perhaloalkyl, nitro, amino, a         diazo salt, optionally substituted lower alkyl, optionally         substituted lower alkylene, optionally substituted lower alkoxy,         optionally substituted lower alkoxyalkyl, optionally substituted         lower alkoxyalkoxy, optionally substituted lower mercaptyl,         optionally substituted lower mercaptoalkyl, optionally         substituted lower mercaptomercaptyl, —C(O)OH, —OC(O)H, —C(O)OR,         —OC(O)R, —C(S)OR, —OC(S)R, —C(O)SR, —SC(O)R, —C(S)SR, —SC(S)R,         C-amido, N-amido, and optionally substituted five- or         six-membered heteroaryl ring or optionally substituted         six-membered aryl or heteroaryl ring,         -   where the lower alkyl and the lower alkylene moieties are             each independently and optionally substituted with one or             more substituents selected from the group consisting of             halogen, perhaloalkyl, nitro, amino, hydroxy, alkoxy,             sulfhydryl, thioether, cyano, amido, ester, and

-   -   -   -   where A is selected from the group consisting of oxygen,                 sulfur, and -NH and R₁₂ is selected for the group                 consisting of hydrogen, hydroxy, alkoxy, haloalkoxy,                 halogen, haloalkyl, perhaloalkyl, nitro, amino, and a                 diazo salt, and n is between 0-4; and

        -   where the ring moieties are each independently and             optionally substituted with one or more substituents             selected from the group consisting of lower alkyl, lower             alkylene,

    -   c) R₁₀ and R₁₁ in the compound of Formula I are each         independently selected from the group consisting of hydrogen and         lower alkyl;         provided that:

    -   when R₁ is C₁₅H₃₁, R₂ and R₃ are both CH₃, R₄ is C(O)OCH(CH₃)₂,         and R₆ is either OCH₃, OCH₂CH₃, or OCH(CH₃)₂, then R₅ is not         C(O)OCH₃, C(O)OCH₂CH₃, or C(O)OCH(CH₃)₂; or

    -   when R₁ is C₁₅H₃₁, R₂ and R₃ are both CH₃, R₄ is C(O)OCH₂CH₃,         and R₆ is either OCH₃ or OCH₂CH₃, then R₅ is not C(O)OCH₃ or         C(O)OCH₂CH₃; or

    -   when R₁ is C₁₅H₃₁, R₂ and R₃ are both CH₃, R₆ is OCH(CH₃)₂, and         R₄ is either C(O)OCH₃ or C(O)OCH₂CH₃, then R₅ is not C(O)OCH₃ or         C(O)OCH₂CH₃.

The term “pharmaceutically acceptable salt” refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. Pharmaceutical salts can be obtained by reacting a compound of the invention with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. Pharmaceutical salts can also be obtained by reacting a compound of the invention with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like.

The term “ester” refers to a chemical moiety with formula —(R)_(n)—COOR′, where R and R′ are optionally substituted and are independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), and where n is 0 or 1.

An “amide” is a chemical moiety with formula —(R)_(n)—C(O)NHR′ or —(R)_(n)—NHC(O)R′, where R and R′ are optionally substituted and are independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), and where n is 0 or 1. An amide may beg an amino acid or a peptide molecule attached to a molecule of the present invention, thereby forming a prodrug.

Any amine, hydroxy, or carboxyl side chain on the compounds of the present invention can be esterified or amidified. The procedures and specific groups to be used to achieve this end is known to those of skill in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3^(rd) Ed., John Wiley & Sons, New York, N.Y., 1999, which is incorporated herein by reference in its entirety.

A “prodrug” refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. An example, without limitation, of a prodrug would be a compound of the present invention which is administered as an ester (the “prodrug”) to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial. A further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety.

The term “aromatic” refers to an aromatic group which has at least one ring having a conjugated pi electron system and includes both carbocyclic aryl (e.g., phenyl) and heterocyclic aryl groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups. The term “carbocyclic” refers to a compound which contains one or more covalently closed ring structures, and that the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic from heterocyclic rings in which the ring backbone contains at least one atom which is different from carbon. The term “heteroaromatic” refers to an aromatic group which contains at least one heterocyclic ring.

As used herein, the term “alkyl” refers to an aliphatic hydrocarbon group. The alkyl moiety may be a “saturated alkyl” group, which means that it does not contain any alkene or alkyne moieties. The alkyl moiety may also be an “unsaturated alkyl” moiety, which means that it contains at least one alkene or alkyne moiety. An “alkene” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond, and an “alkyne” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon triple bond. The alkyl moiety, whether saturated or unsaturated, may be branched, straight chain, or cyclic.

The alkyl group may have 1 to 40 carbon atoms (whenever it appears herein, a numerical range such as “1 to 40” refers to each integer in the given range; e.g., “1 to 40 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 40 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated). The alkyl group may also be a medium size alkyl having 1 to 20 carbon atoms. The alkyl group could also be a lower alkyl having 1 to 5 carbon atoms. The alkyl group of the compounds of the invention may be designated as “C₁-C₄ alkyl” or similar designations. By way of example only, “C₁-C₄ alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethly, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.

The alkyl group may be substituted or unsubstituted. When substituted, the substituent group(s) is(are) one or more group(s) individually and independently selected from cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. Wherever a substituent is described as being “optionally substituted” that substituent may be substituted with one of the above substituents.

The substituent “R” or “R′” appearing by itself and without a number designation refers to an optionally substituted substituent selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon).

An “alkoxy” group refers to a RO— group, where R is as defined herein.

An “alkoxyalkyl” group refers to a R′OR— group, where R and R′are as defined herein.

An “alkoxyalkoxy” group refers to a ROR′O— group, where R is as defined herein.

An “mercaptyl” group refers to a RS— group, where R is as defined herein.

An “mercaptoalkyl” group refers to a R′SR— group, where R and R′are as defined herein.

An “mercaptomercaptyl” group refers to a RSR′S— group, where R is as defined herein.

An “O-carboxy” group refers to a RC(═O)O— group, where R is as defined herein.

A “C-carboxy” group refers to a —C(═O)OR groups where R is as defined herein.

An “acetyl” group refers to a —C(═O)CH₃, group.

A “trihalomethanesulfonyl” group refers to a X₃CS(═O)₂— group where X is a halogen.

A “cyano” group refers to a —CN group.

An “isocyanato” group refers to a —NCO group.

A “thiocyanato” group refers to a —CNS group.

An “isothiocyanato” group refers to a —NCS group.

A “sulfinyl” group refers to a —S(═O)—R group, with R as defined herein.

A “S-sulfonamido” group refers to a —S(═O)₂NR, group, with R as defined herein.

A “N-sulfonamido” group refers to a RS(═O)₂NH— group with R as defined herein.

A “trihalomethanesulfonamido” group refers to a X₃CS(═O)₂NR— group with X and R as defined herein.

An “O-carbamyl” group refers to a —OC(═O)—NR, group-with R as defined herein.

An “N-carbamyl” group refers to a ROC(═O)NH— group, with R as defined herein.

An “O-thiocarbamyl” group refers to a —OC(═S)—NR, group with R as defined herein.

An “N-thiocarbamyl” group refers to an ROC(═S)NH— group, with R as defined herein.

A “C-amido” group refers to a —C(═O)—NR₂ group with R as defined herein.

An “N-amido” group refers to a RC(═O)NH— group, with R as defined herein.

The term “perhaloalkyl” refers to an alkyl group where all of the hydrogen atoms are replaced by halogen atoms.

Unless otherwise indicated, when a substituent is deemed to be “optionally substituted,” it is meant that the substituent is a group that may be substituted with one or more group(s) individually and independently selected from cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof. The protecting groups that may form the protective derivatives of the above substituents are known to those of skill in the art and may be found in references such as Greene and Wuts, above.

In certain embodiments, in the compound of Formula I or II, R₁ is an optionally substituted alkyl group having greater than or equal to ten carbon atoms. In other embodiments, R₁ has greater than or equal to twelve carbon atoms, whereas in other embodiments, R₁ has greater than or equal to fifteen carbon atoms. In some embodiments, R₁ is a C₁₀ straight-chain alkyl group, or a C₁₁ straight-chain alkyl group, or a C₁₂ straight-chain alkyl group, or a C₁₃ straight-chain alkyl group, or a C₁₄ straight-chain alkyl group, or a C₁₅ straight-chain alkyl group. In certain embodiments

In certain embodiments, R₂ and R₃ are each independently an optionally substituted alkyl group. In some embodiments, R₂ and R₃ are the same, whereas in other embodiments, they are different. In certain embodiments, R₂ and R₃ are lower alkyl. In certain compounds of Formula I or II, R₂ and R₃ are each independently selected from methyl, ethyl, or isopropyl. Embodiments of the present invention include those in which R₂ and R₃ are the same and they both are methyl.

In certain embodiments, R₄ is

where A is selected from the group consisting of oxygen, sulfur, and —NH and R₁₂ is selected from the group consisting of hydrogen, hydroxy, alkoxy, haloalkoxy, halogen, haloalkyl, perhaloalkyl, nitro, amino, and a diazo salt, and n is between 0-4.

A “diazo salt” is a group of formula —NN⁺X⁻, where X is a halogen. In some embodiments, the halogen is a chlorine, while in other embodiments, the halogen is a fluorine, or a bromine.

In some embodiments A is oxygen, while in other embodiments A is sulfur, and in still other embodiments A is —NH.

R⁴ and R₅ may be the same or different. In some embodiments, R₄ and R₅ are selected from the group consisting of

-   -   a) an optionally substituted alkyl group;     -   b) an alkoxy of formula —(X₁)_(n1)—O—X₂, where         -   X₁ is selected from the group consisting of lower alkylene,             lower alkenylene, lower alkynylene, aryl, and heteroaryl;         -   X₂ is selected from the group consisting of hydrogen, lower             alkyl, aryl, and heteroaryl; and         -   n1 is 0 or 1; and     -   c) a thioether or thiol of formula —(X₃)_(n3)—S—X₄, where         -   X₃ is selected from the group consisting of lower alkylene,             lower alkenylene, lower alkynylene, aryl, and heteroaryl;         -   X₄ is selected from the group consisting of hydrogen, lower             alkyl, aryl, and heteroaryl; and         -   n3 is 0 or 1;     -   d) a carboxylic acid of formula —(X₅)_(n5)—C(═E)—E′H, where         -   X₅ is selected from the group consisting of lower alkylene,             lower alkenylene, lower alkynylene, aryl, and heteroaryl;         -   E and E′ are each independently selected from the group             consisting of oxygen and sulfur;         -   n5 is 0 or 1; and     -   e) an ester of formula —(X₆)_(n6)—C(═E)—E′X₇, or of formula         —(X₆)_(n6)—E′—C(═E)—X₇, where         -   X₆ is selected from the group consisting of lower alkylene,             lower alkenylene, lower alkynylene, aryl, and heteroaryl;         -   E and E′ are each independently selected from the group             consisting of oxygen and sulfur;         -   X₇ is selected from the group consisting of hydrogen, lower             alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino, and —NX₈X₉,             -   where X₈ and X₉ are each independently selected from the                 group consisting of hydrogen, alkyl, aryl, and                 heteroaryl; and         -   n6 is 0 or 1.

In some embodiments, R₄ and R₅ are each independently lower alkyl. In certain embodiments, R₄ and R₅ are selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl.

In other embodiments, where n1, n3, n5, or n6 in the above formulae is each independently 1, then X₁, X₃, X₅, and X₆ are each independently methylene (—CH₂—). In certain embodiments, X₂, X₄, and X₇ are each independently lower alkyl. The lower alkyl may be selected from the group consisting of methyl, ethyl, and isopropyl.

In certain embodiments, E and E′ are each independently oxygen, whereas in other embodiments E may be sulfur and E′, if it exists, oxygen.

In certain embodiments, R₄ and R₅ are each independently selected from the group consisting of —C(O)OH, —C(O)OCH₃, —C(O)OCH₂CH₃, —C(O)OCH(CH₃)₂, —CH₂OCH₃, —CH₂OCH₂CH₃, and —CH₂OCH(CH₃)₂.

In certain embodiments, R₆ is selected from the group consisting of

-   -   a) hydrogen;     -   b) an optionally substituted alkyl group;     -   c) an alkoxy of formula —(X₁)_(n1)—O—X₂, where         -   X₁ is selected from the group consisting of lower alkylene,             lower alkenylene, lower alkynylene, aryl, and heteroaryl;         -   X₂ is selected from the group consisting of hydrogen, lower             alkyl, aryl, and heteroaryl; and         -   n1 is 0 or 1; and     -   d) a thioether or thiol of formula —(X₃)_(n3)—S—X₄, where         -   X₃ is selected from the group consisting of lower alkylene,             lower alkenylene, lower alkynylene, aryl, and heteroaryl;         -   X₄ is selected from the group consisting of hydrogen, lower             alkyl, aryl, and heteroaryl; and         -   n3 is 0 or 1;     -   e) a carboxylic acid of formula —(X₅)_(n5)—C(═E)—E′H, where         -   X₅ is selected from the group consisting of lower alkylene,             lower alkenylene, lower alkynylene, aryl, and heteroaryl;         -   E and E′ are each independently selected from the group             consisting of oxygen and sulfur;         -   n5 is 0 or 1; and     -   f) an ester of formula —(X₆)_(n6)—C(═E)—E′X₇, or of formula         —(X₆)_(n6)—E′—C(═E)—X₇, where         -   X₆ is selected from the group consisting of lower alkylene,             lower alkenylene, lower alkynylene, aryl, and heteroaryl;         -   E and E′ are each independently selected from the group             consisting of oxygen and sulfur;         -   X₇ is selected from the group consisting of hydrogen, lower             alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino, and —NX₈X₉,             -   where X₈ and X₉ are each independently selected from the                 group consisting of hydrogen, alkyl, aryl, and                 heteroaryl; and         -   n6 is 0 or 1.

In certain embodiments, the alkyl mentioned above is a lower alkyl. In some of these embodiments, the alkyl is selected from the group consisting of methyl, ethyl, and isopropyl. In certain other embodiments, R₆ is an alkoxy selected from the group consisting of methoxy, ethoxy, and isopropoxy.

In certain embodiments R₇-R₉ are each independently selected from the group consisting of

-   -   a) hydrogen;     -   b) an optionally substituted alkyl group;     -   c) an alkoxy of formula —(X₁)_(n1)—O—X₂, where         -   X₁ is selected from the group consisting of lower alkylene,             lower alkenylene, lower alkynylene, aryl, and heteroaryl;         -   X₂ is selected from the group consisting of hydrogen, lower             alkyl, aryl, and heteroaryl; and         -   n1 is 0 or 1; and     -   d) a thioether or thiol of formula —(X₃)_(n3)—S—X₄, where         -   X₃ is selected from the group consisting of lower alkylene,             lower alkenylene, lower alkynylene, aryl, and heteroaryl;         -   X₄ is selected from the group consisting of hydrogen, lower             alkyl, aryl, and heteroaryl; and         -   n3 is 0 or 1;     -   e) a carboxylic acid of formula —(X₅)_(n5)—C(═E)—E′H, where         -   X₅ is selected from the group consisting of lower alkylene,             lower alkenylene, lower alkynylene, aryl, and heteroaryl;         -   E and E′ are each independently selected from the group             consisting of oxygen and sulfur;         -   n5 is 0 or 1;     -   f) an ester of formula —(X₆)_(n6)—C(═E)—E′X₇, or of formula         —(X₆)_(n6)—E′—C(═E)—X₇, where         -   X₆ is selected from the group consisting of lower alkylene,             lower alkenylene, lower alkynylene, aryl, and heteroaryl;         -   E and E′ are each independently selected from the group             consisting of oxygen and sulfur;         -   X₇ is selected from the group consisting of hydrogen, lower             alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino, and —NX₈X₉,             -   where X₈ and X₉ are each independently selected from the                 group consisting of hydrogen, alkyl, aryl, and                 heteroaryl; and         -   n6 is 0 or 1;     -   g) an amine of formula —(X₁₀)_(n10)—NX₁₁X₁₂, where         -   X₁₀ is selected from the group consisting of lower alkylene,             lower alkenylene, lower alkynylene, aryl, and heteroaryl;         -   where X₁₀ and X₁₁ are each independently selected from the             group consisting of hydrogen, alkyl, aryl, and heteroaryl;             and         -   n10 is 0 or 1;     -   h) NO₂;     -   i) halogen or perhaloalkyl; and     -   j) CN.

In certain embodiments, the alkyl mentioned above is a lower alkyl. In some of these embodiments, the alkyl is selected from the group consisting of methyl, ethyl, and isopropyl. In certain other embodiments, R₇-R₉ are each independently hydrogen, hydroxy, cyano (CN), nitro (NO₂), amino (NH₂), methyl, ethyl, isopropyl, fluoro, and chloro. It is understood that in some embodiments R₇-R₉ are the same, whereas in other embodiments, R₇-R₉ are different.

In certain embodiments R₁₀ and R₁₁ are each independently selected from the group consisting of hydrogen and alkyl. In certain embodiments, the alkyl is a lower alkyl. In some of these embodiments, the alkyl is selected from the group consisting of methyl, ethyl, and isopropyl.

The compounds of the present invention are shown here without designating any particular stereochemistry. Some of the compounds of the present invention posses a chiral center and exhibit optical isomerism. It is understood that the scope of the present invention includes a racemic mixture of the isomer, in addition to the individual S and R isomers of the compounds disclosed herein. Separation of optical isomers from a racemic mixture can be accomplished using methods known to those of ordinary skill in the art.

In certain embodiments, the present invention relates to a compound of Formula I or II, where the compound is selected from the group consisting of

-   -   diethyl         1,4-dihydro-4-(2′-ethoxy-6′-pentadecylphenyl)-2,6-dimethyl-3,5-pyridine         dicarboxylate;     -   dimethyl         1,4-dihydro-4-(2′-ethoxy-6′-pentadecylphenyl)-2,6-dimethyl-3,5-pyridine         dicarboxylate;     -   diisopropyl         1,4-dihydro-4-(2′-ethoxy-6′-pentadecylphenyl)-2,6-dimethyl-3,5-pyridine         dicarboxylate;     -   diethyl         1,4-dihydro-4-(2′-methoxy-6′-pentadecylphenyl)-2,6-dimethyl-3,5-pyridine         dicarboxylate;     -   dimethyl         1,4-dihydro-4-(2′-methoxy-6′-pentadecylphenyl)-2,6-dimethyl-3,5-pyridine         dicarboxylate;     -   diisopropyl         1,4-dihydro-4-(2′-methoxy-6′-pentadecylphenyl)-2,6-dimethyl-3,5-carboxypyridine         dicarboxylate;     -   diethyl         1,4-dihydro-4-(2′-isopropoxy-6′-pentadecylphenyl)-2,6-dimethyl-3,5-pyridine         dicarboxylate;     -   dimethyl         1,4-dihydro-4-(2′-isopropoxy-6′-pentadecylphenyl)-2,6-dimethyl-3,5-pyridine         dicarboxylate;     -   diisopropyl         1,4-dihydro-4-(2′-isopropoxy-6′-pentadecylphenyl)-2,6-dimethyl-3,5-pyridine         dicarboxylate;     -   diethyl         1,4-dihydro-4-(2′-methoxy-6′-pentadecylphenyl)-2-methyl-6-(2′-mercapto-1′H-benzimidazolyl)methyl-3,5-pyridine         dicarboxylate;     -   dimethyl         1,4-dihydro-4-(2′-methoxy-6′-pentadecylphenyl)-2-methyl-6-(2′-mercapto-1′H-benzimidazolyl)methyl-3,5-pyridine         dicarboxylate;     -   diisopropyl         1,4-dihydro-4-(2′-methoxy-6′-pentadecylphenyl)-2-methyl-6-(2′-mercapto-1′H-benzimidazolyl)methyl-3,5-pyridine         dicarboxylate;     -   diethyl         1,4-dihydro-4-(2′-isopropoxy-6′-pentadecylphenyl)-2-methyl-6-(2′-mercapto-1′H-benzimidazolyl)methyl-3,5-pyridine         dicarboxylate;     -   dimethyl         1,4-dihydro-4-(2′-isopropoxy-6′-pentadecylphenyl)-2-methyl-6-(2′-mercapto-1′H-benzimidazolyl)methyl-3,5-pyridine         dicarboxylate;     -   diisopropyl         1,4-dihydro-4-(2′-isopropoxy-6′-pentadecylphenyl)-2-methyl-6-(2′-mercapto-1′H-benzimidazolyl)methyl-3,5-pyridine         dicarboxylate;     -   diethyl         1,4-dihydro-4-(2′-ethoxy-6′-pentadecylphenyl)-2-methyl-6-(2′-mercapto-1′H-benzimidazolyl)methyl-3,5-pyridine         dicarboxylate;     -   dimethyl         1,4-dihydro-4-(2′-ethoxy-6′-pentadecylphenyl)-2-methyl-6-(2′-mercapto-1′H-benzimidazolyl)methyl-3,5-pyridine         dicarboxylate;     -   diisopropyl         1,4-dihydro-4-(2′-ethoxy-6′-pentadecylphenyl)-2-methyl-6-(2′-mercapto-1′H-benzimidazolyl)methyl-3,5-pyridine         dicarboxylate;     -   1,4-dihydro-4-(2′-ethoxy-6′-pentadecylphenyl)-2,6-dimethyl-3-ethyl-5-(methoxyethyl)pyridine         dicarboxylate;     -   1,4-dihydro-4-(2′-ethoxy-6′-pentadecylphenyl)-2,6-dimethyl-3-methyl-5-(methoxyethyl)pyridine         dicarboxylate;     -   1,4-dihydro-4-(2′-ethoxy-6′-pentadecylphenyl)-2,6-dimethyl-3-isopropyl-5-(methoxyethyl)pyridine         dicarboxylate;     -   1,4-dihydro-4-(2′-methoxy-6′-pentadecylphenyl)-2,6-dimethyl-3-ethyl-5-(methoxyethyl)pyridine         dicarboxylate;     -   1,4-dihydro-4-(2′-isopropoxy-6′-pentadecylphenyl)-2,6-dimethyl-3-ethyl-5-(methoxyethyl)pyridine         dicarboxylate;     -   diethyl         1,4-dihydro-4-(2′-ethoxy-6′-pentadecylphenyl)-2-(2′-aminoethoxy)methyl-6-methyl-3,5-pyridine         dicarboxylate;     -   dimethyl         1,4-dihydro-4-(2′-ethoxy-6′-pentadecylphenyl)-2-(2′-aminoethoxy)methyl-6-methyl-3,5-pyridine         dicarboxylate;     -   diisopropyl         1,4-dihydro-4-(2′-ethoxy-6′-pentadecylphenyl)-2-(2′-aminoethoxy)methyl-6-methyl-3,5-pyridine         dicarboxylate;     -   diethyl         1,4-dihydro-4-(2′-methoxy-6′-pentadecylphenyl)-2-(2′-aminoethoxy)methyl-6-methyl-3,5-pyridine         dicarboxylate;     -   dimethyl         1,4-dihydro-4-(2′-methoxy-6′-pentadecylphenyl)-2-(2′-aminoethoxy)methyl-6-methyl-3,5-pyridine         dicarboxylate;     -   diisopropyl         1,4-dihydro-4-(2′-methoxy-6′-pentadecylphenyl)-2-(2′-aminoethoxy)methyl-6-methyl-3,5-pyridine         dicarboxylate;     -   diethyl         1,4-dihydro-4-(2′-isopropoxy-6′-pentadecylphenyl)-2-((2′-aminoethoxy)methyl-6-methyl-3,5-pyridine         dicarboxylate;     -   dimethyl         1,4-dihydro-4-(2′-isopropoxy-6′-pentadecylphenyl)-2-(2′-aminoethoxy)methyl-6-methyl-3,5-pyridine         dicarboxylate;     -   diisopropyl         1,4-dihydro-4-(2′-isopropoxy-6′-pentadecylphenyl)-2-(2′-aminoethoxy)methyl-6-methyl-3,5-pyridine         dicarboxylate;     -   diethyl         1,4-dihydro-4-(2′-ethoxy-3′,5′-dinitro-6′-pentadecylphenyl)-2,6-dimethyl-3,5-pyridine         dicarboxylate;     -   dimethyl         1,4-dihydro-4-(2′-ethoxy-3′,5′-dinitro-6′-pentadecylphenyl)-2,6-dimethyl-3,5-pyridine         dicarboxylate;     -   diisopropyl         1,4-dihydro-4-(2′-ethoxy-3′,5′-dinitro-6′-pentadecylphenyl)-2,6-dimethyl-3,5-pyridine         dicarboxylate;     -   diethyl         1,4-dihydro-4-(2′-methoxy-3′,5′-dinitro-6′-pentadecylphenyl)-2,6-dimethyl-3,5-pyridine         dicarboxylate;     -   dimethyl         1,4-dihydro-4-(2′-methoxy-3′,5′-dinitro-6′-pentadecylphenyl)-2,6-dimethyl-3,5-pyridine         dicarboxylate;     -   diisopropyl         1,4-dihydro-4-(2′-methoxy-3′,5′-dinitro-6′-pentadecylphenyl)-2,6-dimethyl-3,5-pyridine         dicarboxylate;     -   diethyl         1,4-dihydro-4-(2′-isopropoxy-3′,5′-dinitro-6′-pentadecylphenyl)-2,6-dimethyl-3,5-pyridine         dicarboxylate;     -   dimethyl         1,4-dihydro-4-(2′-isopropoxy-3′,5′-dinitro-6′-pentadecylphenyl)-2,6-dimethyl-3,5-pyridine         dicarboxylate;     -   diisopropyl         1,4-dihydro-4-(2′-isopropoxy-3′,5′-dinitro-6′-pentadecylphenyl)-2,6-dimethyl-3,5-pyridine         dicarboxylate;     -   diethyl         1,4-dihydro-4-(2′-ethoxy-3′,5′-diamino-6′-pentadecylphenyl)-2,6-dimethyl-3,5-pyridine         dicarboxylate;     -   dimethyl         1,4-dihydro-4-(2′-ethoxy-3′,5′-diamino-6′-pentadecylphenyl)-2,6-dimethyl-3,5-pyridine         dicarboxylate;     -   diisopropyl         1,4-dihydro-4-(2′-ethoxy-3′,5′-diamino-6′-pentadecylphenyl)-2,6-dimethyl-3,5-pyridine         dicarboxylate;     -   diethyl         1,4-dihydro-4-(2′-methoxy-3′,5′-diamino-6′-pentadecylphenyl)-2,6-dimethyl-3,5-pyridine         dicarboxylate;     -   dimethyl         1,4-dihydro-4-(2′-methoxy-3′,5′-diamino-6′-pentadecylphenyl)-2,6-dimethyl-3,5-pyridine         dicarboxylate;     -   diisopropyl         1,4-dihydro-4-(2′-methoxy-3′,5′-diamino-6′-pentadecylphenyl)-2,6-dimethyl-3,5-pyridine         dicarboxylate;     -   diethyl         1,4-dihydro-4-(2′-isopropoxy-3′,5′-diamino-6′-pentadecylphenyl)-2,6-dimethyl-3,5-pyridine         dicarboxylate;     -   dimethyl         1,4-dihydro-4-(2′-isopropoxy-3′,5′-diamino-6′-pentadecylphenyl)-2,6-dimethyl-3,5-pyridine         dicarboxylate;     -   diisopropyl         1,4-dihydro-4-(2′-isopropoxy-3′,5′-diamino-6′-pentadecylphenyl)-2,6-dimethyl-3,5-pyridine         dicarboxylate;     -   diethyl         1,4-dihydro-4-(2′-ethoxy-6′-pentadecylphenyl)-2-methyl-6-(5″-methyl-2-mercapto-1′H-benzimidazolyl)methyl-3,5-pyridine         dicarboxylate;     -   dimethyl         1,4-dihydro-4-(2′-ethoxy-6′-pentadecylphenyl)-2-methyl-6-(5″-methyl-2-mercapto-1′H-benzimidazolyl)methyl-3,5-pyridine         dicarboxylate;     -   diisopropyl         1,4-dihydro-4-(2′-ethoxy-6′-pentadecylphenyl)-2-methyl-6-(5″-methyl-2-mercapto-1′H-benzimidazolyl)methyl-3,5-pyridine         dicarboxylate;     -   diethyl         1,4-dihydro-4-(2′-methoxy-6′-pentadecylphenyl)-2-methyl-6-(5″-methyl-2-mercapto-1′H-betizimidazolyl)methyl-3,5-pyridine         dicarboxylate;     -   dimethyl         1,4-dihydro-4-(2′-methoxy-6′-pentadecylphenyl)-2-methyl-6-(5″-methyl-2-mercapto-1′H-benzimidazolyl)methyl-3,5-pyridine         dicarboxylate;     -   diisopropyl         1,4-dihydro-4-(2′-methoxy-6′-pentadecylphenyl)-2-methyl-6-(5″-methyl-2-mercapto-1′H-benzimidazolyl)methyl-3,5-pyridine         dicarboxylate;     -   diethyl         1,4-dihydro-4-(2′-isopropoxy-6′-pentadecylphenyl)-2-methyl-6-(5″-methyl-2-mercapto-1′H-benzimidazolyl)methyl-3,5-pyridine         dicarboxylate;     -   dimethyl         1,4-dihydro-4-(2′-isopropoxy-6′-pentadecylphenyl)-2-methyl-6-methyl(5′-methyl-2-mercapto-1′H-benzimidazolyl)methyl-3,5-pyridine         dicarboxylate; and     -   diisopropyl         1,4-dihydro-4-(2′-isopropoxy-6′-pentadecylphenyl)-2-methyl-6-methyl         (5′-methyl-2-mercapto-1′H-benzimidazolyl)methyl-3,5-pyridine         dicarboxylate.

Some of the compounds of the present invention are listed in Table 1, below, and are designated DHP-1 through DHP-655.

TABLE I

Comp'd Number R₁ R₂ R₃ R₄ R₅ R₆ R₇ R₈ R₉ DHP-1 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₃ OCH₃ H H H DHP-2 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH₃ H H H DHP-3 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₃ OCH₂CH₃ H H H DHP-4 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH₂CH₃ H H H DHP-5 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH₃ OCH(CH₃)₂ H H H DHP-6 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₃ OCH(CH₃)₂ H H H DHP-7 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH(CH₃)₂ H H H DHP-8 C₁₅H₃₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₃ OCH₃ H H H DHP-9 C₁₅H₃₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₂CH₃ OCH₃ H H H DHP-10 C₁₅H₃₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH(CH₃)₂ OCH₃ H H H DHP-11 C₁₅H₃₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₃ OCH₂CH₃ H H H DHP-12 C₁₅H₃₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₂CH₃ OCH₂CH₃ H H H DHP-13 C₁₅H₃₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH(CH₃)₂ OCH₂CH₃ H H H DHP-14 C₁₅H₃₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₃ OCH(CH₃)₂ H H H DHP-15 C₁₅H₃₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₂CH₃ OCH(CH₃)₂ H H H DHP-16 C₁₅H₃₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH(CH₃)₂ OCH(CH₃)₂ H H H DHP-17 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH₃ H H H DHP-18 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH₂CH₃ H H H DHP-19 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH₃ OCH₂CH₃ H H H DHP-20 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH₃ OCH₃ H H H DHP-21 C₁₅H₃₁ CH₃ A* C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH₃ H H H DHP-22 C₁₅H₃₁ CH₃ A C(O)OCH₂CH₃ C(O)OCH₃ OCH₃ H H H DHP-23 C₁₅H₃₁ CH₃ A C(O)OCH₂CH₃ C(O)OCH(CH₃)₂ OCH₃ H H H DHP-24 C₁₅H₃₁ CH₃ A C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH(CH₃)₂ H H H DHP-25 C₁₅H₃₁ CH₃ A C(O)OCH₂CH₃ C(O)OCH₃ OCH(CH₃)₂ H H H DHP-26 C₁₅H₃₁ CH₃ A C(O)OCH₂CH₃ C(O)OCH(CH₃)₂ OCH(CH₃)₂ H H H DHP-27 C₁₅H₃₁ CH₃ A C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH₂CH₃ H H H DHP-28 C₁₅H₃₁ CH₃ A C(O)OCH₂CH₃ C(O)OCH₃ OCH₂CH₃ H H H DHP-29 C₁₅H₃₁ CH₃ A C(O)OCH₂CH₃ C(O)OCH(CH₃)₂ OCH₂CH₃ H H H DHP-30 C₁₅H₃₁ CH₃ A C(O)OCH₃ C(O)OCH₃ OCH₃ H H H DHP-31 C₁₅H₃₁ CH₃ A C(O)OCH₃ C(O)OCH₂CH₃ OCH₃ H H H DHP-32 C₁₅H₃₁ CH₃ A C(O)OCH₃ C(O)OCH(CH₃)₂ OCH₃ H H H DHP-33 C₁₅H₃₁ CH₃ A C(O)OCH₃ C(O)OCH₃ OCH(CH₃)₂ H H H DHP-34 C₁₅H₃₁ CH₃ A C(O)OCH₃ C(O)OCH₂CH₃ OCH(CH₃)₂ H H H DHP-35 C₁₅H₃₁ CH₃ A C(O)OCH₃ C(O)OCH(CH₃)₂ OCH(CH₃)₂ H H H DHP-36 C₁₅H₃₁ CH₃ A C(O)OCH₃ C(O)OCH₃ OCH₂CH₃ H H H DHP-37 C₁₅H₃₁ CH₃ A C(O)OCH₃ C(O)OCH₂CH₃ OCH₂CH₃ H H H DHP-38 C₁₅H₃₁ CH₃ A C(O)OCH₃ C(O)OCH(CH₃)₂ OCH₂CH₃ H H H DHP-39 C₁₅H₃₁ CH₃ A C(O)OCH(CH₃)₂ C(O)OCH(CH₃)₂ OCH₃ H H H DHP-40 C₁₅H₃₁ CH₃ A C(O)OCH(CH₃)₂ C(O)OCH₃ OCH₃ H H H DHP-41 C₁₅H₃₁ CH₃ A C(O)OCH(CH₃)₂ C(O)OCH₂CH₃ OCH₃ H H H DHP-42 C₁₅H₃₁ CH₃ A C(O)OCH(CH₃)₂ C(O)OCH(CH₃)₂ OCH(CH₃)₂ H H H DHP-43 C₁₅H₃₁ CH₃ A C(O)OCH(CH₃)₂ C(O)OCH₃ OCH(CH₃)₂ H H H DHP-44 C₁₅H₃₁ CH₃ A C(O)OCH(CH₃)₂ C(O)OCH₂CH₃ OCH(CH₃)₂ H H H DHP-45 C₁₅H₃₁ CH₃ A C(O)OCH(CH₃)₂ C(O)OCH(CH₃)₂ OCH₂CH₃ H H H DHP-46 C₁₅H₃₁ CH₃ A C(O)OCH(CH₃)₂ C(O)OCH₃ OCH₂CH₃ H H H DHP-47 C₁₅H₃₁ CH₃ A C(O)OCH(CH₃)₂ C(O)OCH₂CH₃ OCH₂CH₃ H H H DHP-48 C₁₅H₃₁ CH₃ A C(O)OH C(O)OH OCH₃ H H H DHP-49 C₁₅H₃₁ CH₃ A C(O)OH C(O)OCH₃ OCH₃ H H H DHP-50 C₁₅H₃₁ CH₃ A C(O)OH C(O)OCH₂CH₃ OCH₃ H H H DHP-51 C₁₅H₃₁ CH₃ A C(O)OH C(O)OCH(CH₃)₂ OCH₃ H H H DHP-52 C₁₅H₃₁ CH₃ A C(O)OH C(O)OH OCH(CH₃)₂ H H H DHP-53 C₁₅H₃₁ CH₃ A C(O)OH C(O)OCH₃ OCH(CH₃)₂ H H H DHP-54 C₁₅H₃₁ CH₃ A C(O)OH C(O)OCH₂CH₃ OCH(CH₃)₂ H H H DHP-55 C₁₅H₃₁ CH₃ A C(O)OH C(O)OCH(CH₃)₂ OCH(CH₃)₂ H H H DHP-56 C₁₅H₃₁ CH₃ A C(O)OH C(O)OH OCH₂CH₃ H H H DHP-57 C₁₅H₃₁ CH₃ A C(O)OH C(O)OCH₃ OCH₂CH₃ H H H DHP-58 C₁₅H₃₁ CH₃ A C(O)OH C(O)OCH₂CH₃ OCH₂CH₃ H H H DHP-59 C₁₅H₃₁ CH₃ A C(O)OH C(O)OCH(CH₃)₂ OCH₂CH₃ H H H DHP-60 C₁₅H₃₁ CH₃ A C(O)OCH₃ C(O)OH OCH₃ H H H DHP-61 C₁₅H₃₁ CH₃ A C(O)OCH₂CH₃ C(O)OH OCH₃ H H H DHP-62 C₁₅H₃₁ CH₃ A C(O)OCH(CH₃)₂ C(O)OH OCH₃ H H H DHP-63 C₁₅H₃₁ CH₃ A C(O)OCH₃ C(O)OH OCH(CH₃)₂ H H H DHP-64 C₁₅H₃₁ CH₃ A C(O)OCH₂CH₃ C(O)OH OCH(CH₃)₂ H H H DHP-65 C₁₅H₃₁ CH₃ A C(O)OCH(CH₃)₂ C(O)OH OCH(CH₃)₂ H H H DHP-66 C₁₅H₃₁ CH₃ A C(O)OCH₃ C(O)OH OCH₂CH₃ H H H DHP-67 C₁₅H₃₁ CH₃ A C(O)OCH₂CH₃ C(O)OH OCH₂CH₃ H H H DHP-68 C₁₅H₃₁ CH₃ A C(O)OCH(CH₃)₂ C(O)OH OCH₂CH₃ H H H DHP-69 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₂OCH₃ C(O)OCH₂CH₃ OCH₂CH₃ H H H DHP-70 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₂OCH₃ C(O)OCH₃ OCH₂CH₃ H H H DHP-71 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₂OCH₃ C(O)OCH(CH₃)₂ OCH₂CH₃ H H H DHP-72 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₂OCH₃ C(O)OCH₂CH₃ OCH(CH₃)₂ H H H DHP-73 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₂OCH₃ C(O)OCH₃ OCH(CH₃)₂ H H H DHP-74 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₂OCH₃ C(O)OCH(CH₃)₂ OCH(CH₃)₂ H H H DHP-75 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₂OCH₃ C(O)OCH₂CH₃ OCH₃ H H H DHP-76 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₂OCH₃ C(O)OCH₃ OCH₃ H H H DHP-77 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₂OCH₃ C(O)OCH(CH₃)₂ OCH₃ H H H DHP-78 C₁₅H₃₁ B** CH₃ C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH₃ H H H DHP-79 C₁₅H₃₁ B CH₃ C(O)OCH₂CH₃ C(O)OCH₃ OCH₃ H H H DHP-80 C₁₅H₃₁ B CH₃ C(O)OCH₂CH₃ C(O)OCH(CH₃)₂ OCH₃ H H H DHP-81 C₁₅H₃₁ B CH₃ C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH(CH₃)₂ H H H DHP-82 C₁₅H₃₁ B CH₃ C(O)OCH₂CH₃ C(O)OCH₃ OCH(CH₃)₂ H H H DHP-83 C₁₅H₃₁ B CH₃ C(O)OCH₂CH₃ C(O)OCH(CH₃)₂ OCH(CH₃)₂ H H H DHP-84 C₁₅H₃₁ B CH₃ C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH₂CH₃ H H H DHP-85 C₁₅H₃₁ B CH₃ C(O)OCH₂CH₃ C(O)OCH₃ OCH₂CH₃ H H H DHP-86 C₁₅H₃₁ B CH₃ C(O)OCH₂CH₃ C(O)OCH(CH₃)₂ OCH₂CH₃ H H H DHP-87 C₁₅H₃₁ B CH₃ C(O)OCH₃ C(O)OCH₃ OCH₃ H H H DHP-88 C₁₅H₃₁ B CH₃ C(O)OCH₃ C(O)OCH₂CH₃ OCH₃ H H H DHP-89 C₁₅H₃₁ B CH₃ C(O)OCH₃ C(O)OCH(CH₃)₂ OCH₃ H H H DHP-90 C₁₅H₃₁ B CH₃ C(O)OCH₃ C(O)OCH₃ OCH(CH₃)₂ H H H DHP-91 C₁₅H₃₁ B CH₃ C(O)OCH₃ C(O)OCH₂CH₃ OCH(CH₃)₂ H H H DHP-92 C₁₅H₃₁ B CH₃ C(O)OCH₃ C(O)OCH(CH₃)₂ OCH(CH₃)₂ H H H DHP-93 C₁₅H₃₁ B CH₃ C(O)OCH₃ C(O)OCH₃ OCH₂CH₃ H H H DHP-94 C₁₅H₃₁ B CH₃ C(O)OCH₃ C(O)OCH₂CH₃ OCH₂CH₃ H H H DHP-95 C₁₅H₃₁ B CH₃ C(O)OCH₃ C(O)OCH(CH₃)₂ OCH₂CH₃ H H H DHP-96 C₁₅H₃₁ B CH₃ C(O)OCH(CH₃)₂ C(O)OCH(CH₃)₂ OCH₃ H H H DHP-97 C₁₅H₃₁ B CH₃ C(O)OCH(CH₃)₂ C(O)OCH₃ OCH₃ H H H DHP-98 C₁₅H₃₁ B CH₃ C(O)OCH(CH₃)₂ C(O)OCH₂CH₃ OCH₃ H H H DHP-99 C₁₅H₃₁ B CH₃ C(O)OCH(CH₃)₂ C(O)OCH(CH₃)₂ OCH(CH₃)₂ H H H DHP-100 C₁₅H₃₁ B CH₃ C(O)OCH(CH₃)₂ C(O)OCH₃ OCH(CH₃)₂ H H H DHP-101 C₁₅H₃₁ B CH₃ C(O)OCH(CH₃)₂ C(O)OCH₂CH₃ OCH(CH₃)₂ H H H DHP-102 C₁₅H₃₁ B CH₃ C(O)OCH(CH₃)₂ C(O)OCH(CH₃)₂ OCH₂CH₃ H H H DHP-103 C₁₅H₃₁ B CH₃ C(O)OCH(CH₃)₂ C(O)OCH₃ OCH₂CH₃ H H H DHP-104 C₁₅H₃₁ B CH₃ C(O)OCH(CH₃)₂ C(O)OCH₂CH₃ OCH₂CH₃ H H H DHP-105 C₁₅H₃₁ B CH₃ C(O)OH C(O)OH OCH₃ H H H DHP-106 C₁₅H₃₁ B CH₃ C(O)OH C(O)OCH₃ OCH₃ H H H DHP-107 C₁₅H₃₁ B CH₃ C(O)OH C(O)OCH₂CH₃ OCH₃ H H H DHP-108 C₁₅H₃₁ B CH₃ C(O)OH C(O)OCH(CH₃)₂ OCH₃ H H H DHP-109 C₁₅H₃₁ B CH₃ C(O)OH C(O)OH OCH(CH₃)₂ H H H DHP-110 C₁₅H₃₁ B CH₃ C(O)OH C(O)OCH₃ OCH(CH₃)₂ H H H DHP-111 C₁₅H₃₁ B CH₃ C(O)OH C(O)OCH₂CH₃ OCH(CH₃)₂ H H H DHP-112 C₁₅H₃₁ B CH₃ C(O)OH C(O)OCH(CH₃)₂ OCH(CH₃)₂ H H H DHP-113 C₁₅H₃₁ B CH₃ C(O)OH C(O)OH OCH₂CH₃ H H H DHP-114 C₁₅H₃₁ B CH₃ C(O)OH C(O)OCH₃ OCH₂CH₃ H H H DHP-115 C₁₅H₃₁ B CH₃ C(O)OH C(O)OCH₂CH₃ OCH₂CH₃ H H H DHP-116 C₁₅H₃₁ B CH₃ C(O)OH C(O)OCH(CH₃)₂ OCH₂CH₃ H H H DHP-117 C₁₅H₃₁ B CH₃ C(O)OCH₃ C(O)OH OCH₃ H H H DHP-118 C₁₅H₃₁ B CH₃ C(O)OCH₂CH₃ C(O)OH OCH₃ H H H DHP-119 C₁₅H₃₁ B CH₃ C(O)OCH(CH₃)₂ C(O)OH OCH₃ H H H DHP-120 C₁₅H₃₁ B CH₃ C(O)OCH₃ C(O)OH OCH(CH₃)₂ H H H DHP-121 C₁₅H₃₁ B CH₃ C(O)OCH₂CH₃ C(O)OH OCH(CH₃)₂ H H H DHP-122 C₁₅H₃₁ B CH₃ C(O)OCH(CH₃)₂ C(O)OH OCH(CH₃)₂ H H H DHP-123 C₁₅H₃₁ B CH₃ C(O)OCH₃ C(O)OH OCH₂CH₃ H H H DHP-124 C₁₅H₃₁ B CH₃ C(O)OCH₂CH₃ C(O)OH OCH₂CH₃ H H H DHP-125 C₁₅H₃₁ B CH₃ C(O)OCH(CH₃)₂ C(O)OH OCH₂CH₃ H H H DHP-126 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH₃ NO₂ NO₂ H DHP-127 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₃ OCH₃ NO₂ NO₂ H DHP-128 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH(CH₃)₂ OCH₃ NO₂ NO₂ H DHP-129 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH(CH₃)₂ NO₂ NO₂ H DHP-130 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₃ OCH(CH₃)₂ NO₂ NO₂ H DHP-131 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH(CH₃)₂ OCH(CH₃)₂ NO₂ NO₂ H DHP-132 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH₂CH₃ NO₂ NO₂ H DHP-133 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₃ OCH₂CH₃ NO₂ NO₂ H DHP-134 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH(CH₃)₂ OCH₂CH₃ NO₂ NO₂ H DHP-135 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH₃ OCH₃ NO₂ NO₂ H DHP-136 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH₂CH₃ OCH₃ NO₂ NO₂ H DHP-137 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH(CH₃)₂ OCH₃ NO₂ NO₂ H DHP-138 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH₃ OCH(CH₃)₂ NO₂ NO₂ H DHP-139 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH₂CH₃ OCH(CH₃)₂ NO₂ NO₂ H DHP-140 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH(CH₃)₂ OCH(CH₃)₂ NO₂ NO₂ H DHP-141 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH₃ OCH₂CH₃ NO₂ NO₂ H DHP-142 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH₂CH₃ OCH₂CH₃ NO₂ NO₂ H DHP-143 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH(CH₃)₂ OCH₂CH₃ NO₂ NO₂ H DHP-144 C₁₅H₃₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH(CH₃)₂ OCH₃ NO₂ NO₂ H DHP-145 C₁₅H₃₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₃ OCH₃ NO₂ NO₂ H DHP-146 C₁₅H₃₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₂CH₃ OCH₃ NO₂ NO₂ H DHP-147 C₁₅H₃₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH(CH₃)₂ OCH(CH₃)₂ NO₂ NO₂ H DHP-148 C₁₅H₃₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₃ OCH(CH₃)₂ NO₂ NO₂ H DHP-149 C₁₅H₃₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₂CH₃ OCH(CH₃)₂ NO₂ NO₂ H DHP-150 C₁₅H₃₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH(CH₃)₂ OCH₂CH₃ NO₂ NO₂ H DHP-151 C₁₅H₃₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₃ OCH₂CH₃ NO₂ NO₂ H DHP-152 C₁₅H₃₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₂CH₃ OCH₂CH₃ NO₂ NO₂ H DHP-153 C₁₅H₃₁ CH₃ CH₃ C(O)OH C(O)OH OCH₃ NO₂ NO₂ H DHP-154 C₁₅H₃₁ CH₃ CH₃ C(O)OH C(O)OCH₃ OCH₃ NO₂ NO₂ H DHP-155 C₁₅H₃₁ CH₃ CH₃ C(O)OH C(O)OCH₂CH₃ OCH₃ NO₂ NO₂ H DHP-156 C₁₅H₃₁ CH₃ CH₃ C(O)OH C(O)OCH(CH₃)₂ OCH₃ NO₂ NO₂ H DHP-157 C₁₅H₃₁ CH₃ CH₃ C(O)OH C(O)OH OCH(CH₃)₂ NO₂ NO₂ H DHP-158 C₁₅H₃₁ CH₃ CH₃ C(O)OH C(O)OCH₃ OCH(CH₃)₂ NO₂ NO₂ H DHP-159 C₁₅H₃₁ CH₃ CH₃ C(O)OH C(O)OCH₂CH₃ OCH(CH₃)₂ NO₂ NO₂ H DHP-160 C₁₅H₃₁ CH₃ CH₃ C(O)OH C(O)OCH(CH₃)₂ OCH(CH₃)₂ NO₂ NO₂ H DHP-161 C₁₅H₃₁ CH₃ CH₃ C(O)OH C(O)OH OCH₂CH₃ NO₂ NO₂ H DHP-162 C₁₅H₃₁ CH₃ CH₃ C(O)OH C(O)OCH₃ OCH₂CH₃ NO₂ NO₂ H DHP-163 C₁₅H₃₁ CH₃ CH₃ C(O)OH C(O)OCH₂CH₃ OCH₂CH₃ NO₂ NO₂ H DHP-164 C₁₅H₃₁ CH₃ CH₃ C(O)OH C(O)OCH(CH₃)₂ OCH₂CH₃ NO₂ NO₂ H DHP-165 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₃ C(O)OH OCH₃ NO₂ NO₂ H DHP-166 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OH OCH₃ NO₂ NO₂ H DHP-167 C₁₅H₃₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OH OCH₃ NO₂ NO₂ H DHP-168 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₃ C(O)OH OCH(CH₃)₂ NO₂ NO₂ H DHP-169 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OH OCH(CH₃)₂ NO₂ NO₂ H DHP-170 C₁₅H₃₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OH OCH(CH₃)₂ NO₂ NO₂ H DHP-171 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₃ C(O)OH OCH₂CH₃ NO₂ NO₂ H DHP-172 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OH OCH₂CH₃ NO₂ NO₂ H DHP-173 C₁₅H₃₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OH OCH₂CH₃ NO₂ NO₂ H DHP-174 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH₃ NO₂ H H DHP-175 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₃ OCH₃ NO₂ H H DHP-176 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH(CH₃)₂ OCH₃ NO₂ H H DHP-177 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH(CH₃)₂ NO₂ H H DHP-178 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₃ OCH(CH₃)₂ NO₂ H H DHP-179 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH(CH₃)₂ OCH(CH₃)₂ NO₂ H H DHP-180 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH₂CH₃ NO₂ H H DHP-181 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₃ OCH₂CH₃ NO₂ H H DHP-182 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH(CH₃)₂ OCH₂CH₃ NO₂ H H DHP-183 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH₃ OCH₃ NO₂ H H DHP-184 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH₂CH₃ OCH₃ NO₂ H H DHP-185 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH(CH₃)₂ OCH₃ NO₂ H H DHP-186 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH₃ OCH(CH₃)₂ NO₂ H H DHP-187 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH₂CH₃ OCH(CH₃)₂ NO₂ H H DHP-188 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH(CH₃)₂ OCH(CH₃)₂ NO₂ H H DHP-189 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH₃ OCH₂CH₃ NO₂ H H DHP-190 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH₂CH₃ OCH₂CH₃ NO₂ H H DHP-191 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH(CH₃)₂ OCH₂CH₃ NO₂ H H DHP-192 C₁₅H₃₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH(CH₃)₂ OCH₃ NO₂ H H DHP-193 C₁₅H₃₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₃ OCH₃ NO₂ H H DHP-194 C₁₅H₃₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₂CH₃ OCH₃ NO₂ H H DHP-195 C₁₅H₃₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH(CH₃)₂ OCH(CH₃)₂ NO₂ H H DHP-196 C₁₅H₃₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₃ OCH(CH₃)₂ NO₂ H H DHP-197 C₁₅H₃₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₂CH₃ OCH(CH₃)₂ NO₂ H H DHP-198 C₁₅H₃₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH(CH₃)₂ OCH₂CH₃ NO₂ H H DHP-199 C₁₅H₃₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₃ OCH₂CH₃ NO₂ H H DHP-200 C₁₅H₃₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₂CH₃ OCH₂CH₃ NO₂ H H DHP-201 C₁₅H₃₁ CH₃ CH₃ C(O)OH C(O)OH OCH₃ NO₂ H H DHP-202 C₁₅H₃₁ CH₃ CH₃ C(O)OH C(O)OCH₃ OCH₃ NO₂ H H DHP-203 C₁₅H₃₁ CH₃ CH₃ C(O)OH C(O)OCH₂CH₃ OCH₃ NO₂ H H DHP-204 C₁₅H₃₁ CH₃ CH₃ C(O)OH C(O)OCH(CH₃)₂ OCH₃ NO₂ H H DHP-205 C₁₅H₃₁ CH₃ CH₃ C(O)OH C(O)OH OCH(CH₃)₂ NO₂ H H DHP-206 C₁₅H₃₁ CH₃ CH₃ C(O)OH C(O)OCH₃ OCH(CH₃)₂ NO₂ H H DHP-207 C₁₅H₃₁ CH₃ CH₃ C(O)OH C(O)OCH₂CH₃ OCH(CH₃)₂ NO₂ H H DHP-208 C₁₅H₃₁ CH₃ CH₃ C(O)OH C(O)OCH(CH₃)₂ OCH(CH₃)₂ NO₂ H H DHP-209 C₁₅H₃₁ CH₃ CH₃ C(O)OH C(O)OH OCH₂CH₃ NO₂ H H DHP-210 C₁₅H₃₁ CH₃ CH₃ C(O)OH C(O)OCH₃ OCH₂CH₃ NO₂ H H DHP-211 C₁₅H₃₁ CH₃ CH₃ C(O)OH C(O)OCH₂CH₃ OCH₂CH₃ NO₂ H H DHP-212 C₁₅H₃₁ CH₃ CH₃ C(O)OH C(O)OCH(CH₃)₂ OCH₂CH₃ NO₂ H H DHP-213 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₃ C(O)OH OCH₃ NO₂ H H DHP-214 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OH OCH₃ NO₂ H H DHP-215 C₁₅H₃₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OH OCH₃ NO₂ H H DHP-216 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₃ C(O)OH OCH(CH₃)₂ NO₂ H H DHP-217 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OH OCH(CH₃)₂ NO₂ H H DHP-218 C₁₅H₃₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OH OCH(CH₃)₂ NO₂ H H DHP-219 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₃ C(O)OH OCH₂CH₃ NO₂ H H DHP-220 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OH OCH₂CH₃ NO₂ H H DHP-221 C₁₅H₃₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OH OCH₂CH₃ NO₂ H H DHP-222 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH₃ H NO₂ H DHP-223 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₃ OCH₃ H NO₂ H DHP-224 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH(CH₃)₂ OCH₃ H NO₂ H DHP-225 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH(CH₃)₂ H NO₂ H DHP-226 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₃ OCH(CH₃)₂ H NO₂ H DHP-227 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH(CH₃)₂ OCH(CH₃)₂ H NO₂ H DHP-228 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH₂CH₃ H NO₂ H DHP-229 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₃ OCH₂CH₃ H NO₂ H DHP-230 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH(CH₃)₂ OCH₂CH₃ H NO₂ H DHP-231 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH₃ OCH₃ H NO₂ H DHP-232 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH₂CH₃ OCH₃ H NO₂ H DHP-233 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH(CH₃)₂ OCH₃ H NO₂ H DHP-234 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH₃ OCH(CH₃)₂ H NO₂ H DHP-235 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH₂CH₃ OCH(CH₃)₂ H NO₂ H DHP-236 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH(CH₃)₂ OCH(CH₃)₂ H NO₂ H DHP-237 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH₃ OCH₂CH₃ H NO₂ H DHP-238 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH₂CH₃ OCH₂CH₃ H NO₂ H DHP-239 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH(CH₃)₂ OCH₂CH₃ H NO₂ H DHP-240 C₁₅H₃₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH(CH₃)₂ OCH₃ H NO₂ H DHP-241 C₁₅H₃₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₃ OCH₃ H NO₂ H DHP-242 C₁₅H₃₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₂CH₃ OCH₃ H NO₂ H DHP-243 C₁₅H₃₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH(CH₃)₂ OCH(CH₃)₂ H NO₂ H DHP-244 C₁₅H₃₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₃ OCH(CH₃)₂ H NO₂ H DHP-245 C₁₅H₃₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₂CH₃ OCH(CH₃)₂ H NO₂ H DHP-246 C₁₅H₃₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH(CH₃)₂ OCH₂CH₃ H NO₂ H DHP-247 C₁₅H₃₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₃ OCH₂CH₃ H NO₂ H DHP-248 C₁₅H₃₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₂CH₃ OCH₂CH₃ H NO₂ H DHP-249 C₁₅H₃₁ CH₃ CH₃ C(O)OH C(O)OH OCH₃ H NO₂ H DHP-250 C₁₅H₃₁ CH₃ CH₃ C(O)OH C(O)OCH₃ OCH₃ H NO₂ H DHP-251 C₁₅H₃₁ CH₃ CH₃ C(O)OH C(O)OCH₂CH₃ OCH₃ H NO₂ H DHP-252 C₁₅H₃₁ CH₃ CH₃ C(O)OH C(O)OCH(CH₃)₂ OCH₃ H NO₂ H DHP-253 C₁₅H₃₁ CH₃ CH₃ C(O)OH C(O)OH OCH(CH₃)₂ H NO₂ H DHP-254 C₁₅H₃₁ CH₃ CH₃ C(O)OH C(O)OCH₃ OCH(CH₃)₂ H NO₂ H DHP-255 C₁₅H₃₁ CH₃ CH₃ C(O)OH C(O)OCH₂CH₃ OCH(CH₃)₂ H NO₂ H DHP-256 C₁₅H₃₁ CH₃ CH₃ C(O)OH C(O)OCH(CH₃)₂ OCH(CH₃)₂ H NO₂ H DHP-257 C₁₅H₃₁ CH₃ CH₃ C(O)OH C(O)OH OCH₂CH₃ H NO₂ H DHP-258 C₁₅H₃₁ CH₃ CH₃ C(O)OH C(O)OCH₃ OCH₂CH₃ H NO₂ H DHP-259 C₁₅H₃₁ CH₃ CH₃ C(O)OH C(O)OCH₂CH₃ OCH₂CH₃ H NO₂ H DHP-260 C₁₅H₃₁ CH₃ CH₃ C(O)OH C(O)OCH(CH₃)₂ OCH₂CH₃ H NO₂ H DHP-261 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₃ C(O)OH OCH₃ H NO₂ H DHP-262 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OH OCH₃ H NO₂ H DHP-263 C₁₅H₃₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OH OCH₃ H NO₂ H DHP-264 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₃ C(O)OH OCH(CH₃)₂ H NO₂ H DHP-265 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OH OCH(CH₃)₂ H NO₂ H DHP-266 C₁₅H₃₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OH OCH(CH₃)₂ H NO₂ H DHP-267 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₃ C(O)OH OCH₂CH₃ H NO₂ H DHP-268 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OH OCH₂CH₃ H NO₂ H DHP-269 C₁₅H₃₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OH OCH₂CH₃ H NO₂ H DHP-270 C₁₅H₃₁ CH₃ C# C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH₃ H H H DHP-271 C₁₅H₃₁ CH₃ C C(O)OCH₂CH₃ C(O)OCH₃ OCH₃ H H H DHP-272 C₁₅H₃₁ CH₃ C C(O)OCH₂CH₃ C(O)OCH(CH₃)₂ OCH₃ H H H DHP-273 C₁₅H₃₁ CH₃ C C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH(CH₃)₂ H H H DHP-274 C₁₅H₃₁ CH₃ C C(O)OCH₂CH₃ C(O)OCH₃ OCH(CH₃)₂ H H H DHP-275 C₁₅H₃₁ CH₃ C C(O)OCH₂CH₃ C(O)OCH(CH₃)₂ OCH(CH₃)₂ H H H DHP-276 C₁₅H₃₁ CH₃ C C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH₂CH₃ H H H DHP-277 C₁₅H₃₁ CH₃ C C(O)OCH₂CH₃ C(O)OCH₃ OCH₂CH₃ H H H DHP-278 C₁₅H₃₁ CH₃ C C(O)OCH₂CH₃ C(O)OCH(CH₃)₂ OCH₂CH₃ H H H DHP-279 C₁₅H₃₁ CH₃ C C(O)OCH₃ C(O)OCH₃ OCH₃ H H H DHP-280 C₁₅H₃₁ CH₃ C C(O)OCH₃ C(O)OCH₂CH₃ OCH₃ H H H DHP-281 C₁₅H₃₁ CH₃ C C(O)OCH₃ C(O)OCH(CH₃)₂ OCH₃ H H H DHP-282 C₁₅H₃₁ CH₃ C C(O)OCH₃ C(O)OCH₃ OCH(CH₃)₂ H H H DHP-283 C₁₅H₃₁ CH₃ C C(O)OCH₃ C(O)OCH₂CH₃ OCH(CH₃)₂ H H H DHP-284 C₁₅H₃₁ CH₃ C C(O)OCH₃ C(O)OCH(CH₃)₂ OCH(CH₃)₂ H H H DHP-285 C₁₅H₃₁ CH₃ C C(O)OCH₃ C(O)OCH₃ OCH₂CH₃ H H H DHP-286 C₁₅H₃₁ CH₃ C C(O)OCH₃ C(O)OCH₂CH₃ OCH₂CH₃ H H H DHP-287 C₁₅H₃₁ CH₃ C C(O)OCH₃ C(O)OCH(CH₃)₂ OCH₂CH₃ H H H DHP-288 C₁₅H₃₁ CH₃ C C(O)OCH(CH₃)₂ C(O)OCH(CH₃)₂ OCH₃ H H H DHP-289 C₁₅H₃₁ CH₃ C C(O)OCH(CH₃)₂ C(O)OCH₃ OCH₃ H H H DHP-290 C₁₅H₃₁ CH₃ C C(O)OCH(CH₃)₂ C(O)OCH₂CH₃ OCH₃ H H H DHP-291 C₁₅H₃₁ CH₃ C C(O)OCH(CH₃)₂ C(O)OCH(CH₃)₂ OCH(CH₃)₂ H H H DHP-292 C₁₅H₃₁ CH₃ C C(O)OCH(CH₃)₂ C(O)OCH₃ OCH(CH₃)₂ H H H DHP-293 C₁₅H₃₁ CH₃ C C(O)OCH(CH₃)₂ C(O)OCH₂CH₃ OCH(CH₃)₂ H H H DHP-294 C₁₅H₃₁ CH₃ C C(O)OCH(CH₃)₂ C(O)OCH(CH₃)₂ OCH₂CH₃ H H H DHP-295 C₁₅H₃₁ CH₃ C C(O)OCH(CH₃)₂ C(O)OCH₃ OCH₂CH₃ H H H DHP-296 C₁₅H₃₁ CH₃ C C(O)OCH(CH₃)₂ C(O)OCH₂CH₃ OCH₂CH₃ H H H DHP-297 C₁₅H₃₁ CH₃ C C(O)OH C(O)OH OCH₃ H H H DHP-298 C₁₅H₃₁ CH₃ C C(O)OH C(O)OCH₃ OCH₃ H H H DHP-299 C₁₅H₃₁ CH₃ C C(O)OH C(O)OCH₂CH₃ OCH₃ H H H DHP-300 C₁₅H₃₁ CH₃ C C(O)OH C(O)OCH(CH₃)₂ OCH₃ H H H DHP-301 C₁₅H₃₁ CH₃ C C(O)OH C(O)OH OCH(CH₃)₂ H H H DHP-302 C₁₅H₃₁ CH₃ C C(O)OH C(O)OCH₃ OCH(CH₃)₂ H H H DHP-303 C₁₅H₃₁ CH₃ C C(O)OH C(O)OCH₂CH₃ OCH(CH₃)₂ H H H DHP-304 C₁₅H₃₁ CH₃ C C(O)OH C(O)OCH(CH₃)₂ OCH(CH₃)₂ H H H DHP-305 C₁₅H₃₁ CH₃ C C(O)OH C(O)OH OCH₂CH₃ H H H DHP-306 C₁₅H₃₁ CH₃ C C(O)OH C(O)OCH₃ OCH₂CH₃ H H H DHP-307 C₁₅H₃₁ CH₃ C C(O)OH C(O)OCH₂CH₃ OCH₂CH₃ H H H DHP-308 C₁₅H₃₁ CH₃ C C(O)OH C(O)OCH(CH₃)₂ OCH₂CH₃ H H H DHP-309 C₁₅H₃₁ CH₃ C C(O)OCH₃ C(O)OH OCH₃ H H H DHP-310 C₁₅H₃₁ CH₃ C C(O)OCH₂CH₃ C(O)OH OCH₃ H H H DHP-311 C₁₅H₃₁ CH₃ C C(O)OCH(CH₃)₂ C(O)OH OCH₃ H H H DHP-312 C₁₅H₃₁ CH₃ C C(O)OCH₃ C(O)OH OCH(CH₃)₂ H H H DHP-313 C₁₅H₃₁ CH₃ C C(O)OCH₂CH₃ C(O)OH OCH(CH₃)₂ H H H DHP-314 C₁₅H₃₁ CH₃ C C(O)OCH(CH₃)₂ C(O)OH OCH(CH₃)₂ H H H DHP-315 C₁₅H₃₁ CH₃ C C(O)OCH₃ C(O)OH OCH₂CH₃ H H H DHP-316 C₁₅H₃₁ CH₃ C C(O)OCH₂CH₃ C(O)OH OCH₂CH₃ H H H DHP-317 C₁₅H₃₁ CH₃ C C(O)OCH(CH₃)₂ C(O)OH OCH₂CH₃ H H H DHP-318 C₁₅H₃₁ CH₃ CH₃ CH₂OCH₃ CH₂OCH₃ OCH₃ H H H DHP-319 C₁₅H₃₁ CH₃ CH₃ CH₂OCH₃ CH₂OCH₂CH₃ OCH₃ H H H DHP-320 C₁₅H₃₁ CH₃ CH₃ CH₂OCH₃ CH₂OCH(CH₃)₂ OCH₃ H H H DHP-321 C₁₅H₃₁ CH₃ CH₃ CH₂OCH₂CH₃ CH₂OCH₃ OCH(CH₃)₂ H H H DHP-322 C₁₅H₃₁ CH₃ CH₃ CH₂OCH₂CH₃ CH₂OCH₂CH₃ OCH(CH₃)₂ H H H DHP-323 C₁₅H₃₁ CH₃ CH₃ CH₂OCH₂CH₃ CH₂OCH(CH₃)₂ OCH(CH₃)₂ H H H DHP-324 C₁₅H₃₁ CH₃ CH₃ CH₂OCH(CH₃)₂ CH₂OCH₃ OCH₂CH₃ H H H DHP-325 C₁₅H₃₁ CH₃ CH₃ CH₂OCH(CH₃)₂ CH₂OCH₂CH₃ OCH₂CH₃ H H H DHP-326 C₁₅H₃₁ CH₃ CH₃ CH₂OCH(CH₃)₂ CH₂OCH(CH₃)₂ OCH₂CH₃ H H H DHP-327 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₃ OCH₃ H H H DHP-328 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH₃ H H H DHP-329 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₃ OCH₂CH₃ H H H DHP-330 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH₂CH₃ H H H DHP-331 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH₃ OCH(CH₃)₂ H H H DHP-332 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₃ OCH(CH₃)₂ H H H DHP-333 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH(CH₃)₂ H H H DHP-334 C₁₀H₂₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₃ OCH₃ H H H DHP-335 C₁₀H₂₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₂CH₃ OCH₃ H H H DHP-336 C₁₀H₂₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH(CH₃)₂ OCH₃ H H H DHP-337 C₁₀H₂₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₃ OCH₂CH₃ H H H DHP-338 C₁₀H₂₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₂CH₃ OCH₂CH₃ H H H DHP-339 C₁₀H₂₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH(CH₃)₂ OCH₂CH₃ H H H DHP-340 C₁₀H₂₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₃ OCH(CH₃)₂ H H H DHP-341 C₁₀H₂₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₂CH₃ OCH(CH₃)₂ H H H DHP-342 C₁₀H₂₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH(CH₃)₂ OCH(CH₃)₂ H H H DHP-343 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH₃ H H H DHP-344 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH₂CH₃ H H H DHP-345 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH₃ OCH₂CH₃ H H H DHP-346 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH₃ OCH₃ H H H DHP-347 C₁₀H₂₁ CH₃ A* C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH₃ H H H DHP-348 C₁₀H₂₁ CH₃ A C(O)OCH₂CH₃ C(O)OCH₃ OCH₃ H H H DHP-349 C₁₀H₂₁ CH₃ A C(O)OCH₂CH₃ C(O)OCH(CH₃)₂ OCH₃ H H H DHP-350 C₁₀H₂₁ CH₃ A C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH(CH₃)₂ H H H DHP-351 C₁₀H₂₁ CH₃ A C(O)OCH₂CH₃ C(O)OCH₃ OCH(CH₃)₂ H H H DHP-352 C₁₀H₂₁ CH₃ A C(O)OCH₂CH₃ C(O)OCH(CH₃)₂ OCH(CH₃)₂ H H H DHP-353 C₁₀H₂₁ CH₃ A C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH₂CH₃ H H H DHP-354 C₁₀H₂₁ CH₃ A C(O)OCH₂CH₃ C(O)OCH₃ OCH₂CH₃ H H H DHP-355 C₁₀H₂₁ CH₃ A C(O)OCH₂CH₃ C(O)OCH(CH₃)₂ OCH₂CH₃ H H H DHP-356 C₁₀H₂₁ CH₃ A C(O)OCH₃ C(O)OCH₃ OCH₃ H H H DHP-357 C₁₀H₂₁ CH₃ A C(O)OCH₃ C(O)OCH₂CH₃ OCH₃ H H H DHP-358 C₁₀H₂₁ CH₃ A C(O)OCH₃ C(O)OCH(CH₃)₂ OCH₃ H H H DHP-359 C₁₀H₂₁ CH₃ A C(O)OCH₃ C(O)OCH₃ OCH(CH₃)₂ H H H DHP-360 C₁₀H₂₁ CH₃ A C(O)OCH₃ C(O)OCH₂CH₃ OCH(CH₃)₂ H H H DHP-361 C₁₀H₂₁ CH₃ A C(O)OCH₃ C(O)OCH(CH₃)₂ OCH(CH₃)₂ H H H DHP-362 C₁₀H₂₁ CH₃ A C(O)OCH₃ C(O)OCH₃ OCH₂CH₃ H H H DHP-363 C₁₀H₂₁ CH₃ A C(O)OCH₃ C(O)OCH₂CH₃ OCH₂CH₃ H H H DHP-364 C₁₀H₂₁ CH₃ A C(O)OCH₃ C(O)OCH(CH₃)₂ OCH₂CH₃ H H H DHP-365 C₁₀H₂₁ CH₃ A C(O)OCH(CH₃)₂ C(O)OCH(CH₃)₂ OCH₃ H H H DHP-366 C₁₀H₂₁ CH₃ A C(O)OCH(CH₃)₂ C(O)OCH₃ OCH₃ H H H DHP-367 C₁₀H₂₁ CH₃ A C(O)OCH(CH₃)₂ C(O)OCH₂CH₃ OCH₃ H H H DHP-368 C₁₀H₂₁ CH₃ A C(O)OCH(CH₃)₂ C(O)OCH(CH₃)₂ OCH(CH₃)₂ H H H DHP-369 C₁₀H₂₁ CH₃ A C(O)OCH(CH₃)₂ C(O)OCH₃ OCH(CH₃)₂ H H H DHP-370 C₁₀H₂₁ CH₃ A C(O)OCH(CH₃)₂ C(O)OCH₂CH₃ OCH(CH₃)₂ H H H DHP-371 C₁₀H₂₁ CH₃ A C(O)OCH(CH₃)₂ C(O)OCH(CH₃)₂ OCH₂CH₃ H H H DHP-372 C₁₀H₂₁ CH₃ A C(O)OCH(CH₃)₂ C(O)OCH₃ OCH₂CH₃ H H H DHP-373 C₁₀H₂₁ CH₃ A C(O)OCH(CH₃)₂ C(O)OCH₂CH₃ OCH₂CH₃ H H H DHP-374 C₁₀H₂₁ CH₃ A C(O)OH C(O)OH OCH₃ H H H DHP-375 C₁₀H₂₁ CH₃ A C(O)OH C(O)OCH₃ OCH₃ H H H DHP-376 C₁₀H₂₁ CH₃ A C(O)OH C(O)OCH₂CH₃ OCH₃ H H H DHP-377 C₁₀H₂₁ CH₃ A C(O)OH C(O)OCH(CH₃)₂ OCH₃ H H H DHP-378 C₁₀H₂₁ CH₃ A C(O)OH C(O)OH OCH(CH₃)₂ H H H DHP-379 C₁₀H₂₁ CH₃ A C(O)OH C(O)OCH₃ OCH(CH₃)₂ H H H DHP-380 C₁₀H₂₁ CH₃ A C(O)OH C(O)OCH₂CH₃ OCH(CH₃)₂ H H H DHP-381 C₁₀H₂₁ CH₃ A C(O)OH C(O)OCH(CH₃)₂ OCH(CH₃)₂ H H H DHP-382 C₁₀H₂₁ CH₃ A C(O)OH C(O)OH OCH₂CH₃ H H H DHP-383 C₁₀H₂₁ CH₃ A C(O)OH C(O)OCH₃ OCH₂CH₃ H H H DHP-384 C₁₀H₂₁ CH₃ A C(O)OH C(O)OCH₂CH₃ OCH₂CH₃ H H H DHP-385 C₁₀H₂₁ CH₃ A C(O)OH C(O)OCH(CH₃)₂ OCH₂CH₃ H H H DHP-386 C₁₀H₂₁ CH₃ A C(O)OCH₃ C(O)OH OCH₃ H H H DHP-387 C₁₀H₂₁ CH₃ A C(O)OCH₂CH₃ C(O)OH OCH₃ H H H DHP-388 C₁₀H₂₁ CH₃ A C(O)OCH(CH₃)₂ C(O)OH OCH₃ H H H DHP-389 C₁₀H₂₁ CH₃ A C(O)OCH₃ C(O)OH OCH(CH₃)₂ H H H DHP-390 C₁₀H₂₁ CH₃ A C(O)OCH₂CH₃ C(O)OH OCH(CH₃)₂ H H H DHP-391 C₁₀H₂₁ CH₃ A C(O)OCH(CH₃)₂ C(O)OH OCH(CH₃)₂ H H H DHP-392 C₁₀H₂₁ CH₃ A C(O)OCH₃ C(O)OH OCH₂CH₃ H H H DHP-393 C₁₀H₂₁ CH₃ A C(O)OCH₂CH₃ C(O)OH OCH₂CH₃ H H H DHP-394 C₁₀H₂₁ CH₃ A C(O)OCH(CH₃)₂ C(O)OH OCH₂CH₃ H H H DHP-395 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₂OCH₃ C(O)OCH₂CH₃ OCH₂CH₃ H H H DHP-396 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₂OCH₃ C(O)OCH₃ OCH₂CH₃ H H H DHP-397 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₂OCH₃ C(O)OCH(CH₃)₂ OCH₂CH₃ H H H DHP-398 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₂OCH₃ C(O)OCH₂CH₃ OCH(CH₃)₂ H H H DHP-399 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₂OCH₃ C(O)OCH₃ OCH(CH₃)₂ H H H DHP-400 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₂OCH₃ C(O)OCH(CH₃)₂ OCH(CH₃)₂ H H H DHP-401 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₂OCH₃ C(O)OCH₂CH₃ OCH₃ H H H DHP-402 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₂OCH₃ C(O)OCH₃ OCH₃ H H H DHP-403 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₂OCH₃ C(O)OCH(CH₃)₂ OCH₃ H H H DHP-404 C₁₀H₂₁ B** CH₃ C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH₃ H H H DHP-405 C₁₀H₂₁ B CH₃ C(O)OCH₂CH₃ C(O)OCH₃ OCH₃ H H H DHP-406 C₁₀H₂₁ B CH₃ C(O)OCH₂CH₃ C(O)OCH(CH₃)₂ OCH₃ H H H DHP-407 C₁₀H₂₁ B CH₃ C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH(CH₃)₂ H H H DHP-408 C₁₀H₂₁ B CH₃ C(O)OCH₂CH₃ C(O)OCH₃ OCH(CH₃)₂ H H H DHP-409 C₁₀H₂₁ B CH₃ C(O)OCH₂CH₃ C(O)OCH(CH₃)₂ OCH(CH₃)₂ H H H DHP-410 C₁₀H₂₁ B CH₃ C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH₂CH₃ H H H DHP-411 C₁₀H₂₁ B CH₃ C(O)OCH₂CH₃ C(O)OCH₃ OCH₂CH₃ H H H DHP-412 C₁₀H₂₁ B CH₃ C(O)OCH₂CH₃ C(O)OCH(CH₃)₂ OCH₂CH₃ H H H DHP-413 C₁₀H₂₁ B CH₃ C(O)OCH₃ C(O)OCH₃ OCH₃ H H H DHP-414 C₁₀H₂₁ B CH₃ C(O)OCH₃ C(O)OCH₂CH₃ OCH₃ H H H DHP-415 C₁₀H₂₁ B CH₃ C(O)OCH₃ C(O)OCH(CH₃)₂ OCH₃ H H H DHP-416 C₁₀H₂₁ B CH₃ C(O)OCH₃ C(O)OCH₃ OCH(CH₃)₂ H H H DHP-417 C₁₀H₂₁ B CH₃ C(O)OCH₃ C(O)OCH₂CH₃ OCH(CH₃)₂ H H H DHP-418 C₁₀H₂₁ B CH₃ C(O)OCH₃ C(O)OCH(CH₃)₂ OCH(CH₃)₂ H H H DHP-419 C₁₀H₂₁ B CH₃ C(O)OCH₃ C(O)OCH₃ OCH₂CH₃ H H H DHP-420 C₁₀H₂₁ B CH₃ C(O)OCH₃ C(O)OCH₂CH₃ OCH₂CH₃ H H H DHP-421 C₁₀H₂₁ B CH₃ C(O)OCH₃ C(O)OCH(CH₃)₂ OCH₂CH₃ H H H DHP-422 C₁₀H₂₁ B CH₃ C(O)OCH(CH₃)₂ C(O)OCH(CH₃)₂ OCH₃ H H H DHP-423 C₁₀H₂₁ B CH₃ C(O)OCH(CH₃)₂ C(O)OCH₃ OCH₃ H H H DHP-424 C₁₀H₂₁ B CH₃ C(O)OCH(CH₃)₂ C(O)OCH₂CH₃ OCH₃ H H H DHP-425 C₁₀H₂₁ B CH₃ C(O)OCH(CH₃)₂ C(O)OCH(CH₃)₂ OCH(CH₃)₂ H H H DHP-426 C₁₀H₂₁ B CH₃ C(O)OCH(CH₃)₂ C(O)OCH₃ OCH(CH₃)₂ H H H DHP-427 C₁₀H₂₁ B CH₃ C(O)OCH(CH₃)₂ C(O)OCH₂CH₃ OCH(CH₃)₂ H H H DHP-428 C₁₀H₂₁ B CH₃ C(O)OCH(CH₃)₂ C(O)OCH(CH₃)₂ OCH₂CH₃ H H H DHP-429 C₁₀H₂₁ B CH₃ C(O)OCH(CH₃)₂ C(O)OCH₃ OCH₂CH₃ H H H DHP-430 C₁₀H₂₁ B CH₃ C(O)OCH(CH₃)₂ C(O)OCH₂CH₃ OCH₂CH₃ H H H DHP-431 C₁₀H₂₁ B CH₃ C(O)OH C(O)OH OCH₃ H H H DHP-432 C₁₀H₂₁ B CH₃ C(O)OH C(O)OCH₃ OCH₃ H H H DHP-433 C₁₀H₂₁ B CH₃ C(O)OH C(O)OCH₂CH₃ OCH₃ H H H DHP-434 C₁₀H₂₁ B CH₃ C(O)OH C(O)OCH(CH₃)₂ OCH₃ H H H DHP-435 C₁₀H₂₁ B CH₃ C(O)OH C(O)OH OCH(CH₃)₂ H H H DHP-436 C₁₀H₂₁ B CH₃ C(O)OH C(O)OCH₃ OCH(CH₃)₂ H H H DHP-437 C₁₀H₂₁ B CH₃ C(O)OH C(O)OCH₂CH₃ OCH(CH₃)₂ H H H DHP-438 C₁₀H₂₁ B CH₃ C(O)OH C(O)OCH(CH₃)₂ OCH(CH₃)₂ H H H DHP-439 C₁₀H₂₁ B CH₃ C(O)OH C(O)OH OCH₂CH₃ H H H DHP-440 C₁₀H₂₁ B CH₃ C(O)OH C(O)OCH₃ OCH₂CH₃ H H H DHP-441 C₁₀H₂₁ B CH₃ C(O)OH C(O)OCH₂CH₃ OCH₂CH₃ H H H DHP-442 C₁₀H₂₁ B CH₃ C(O)OH C(O)OCH(CH₃)₂ OCH₂CH₃ H H H DHP-443 C₁₀H₂₁ B CH₃ C(O)OCH₃ C(O)OH OCH₃ H H H DHP-444 C₁₀H₂₁ B CH₃ C(O)OCH₂CH₃ C(O)OH OCH₃ H H H DHP-445 C₁₀H₂₁ B CH₃ C(O)OCH(CH₃)₂ C(O)OH OCH₃ H H H DHP-446 C₁₀H₂₁ B CH₃ C(O)OCH₃ C(O)OH OCH(CH₃)₂ H H H DHP-447 C₁₀H₂₁ B CH₃ C(O)OCH₂CH₃ C(O)OH OCH(CH₃)₂ H H H DHP-448 C₁₀H₂₁ B CH₃ C(O)OCH(CH₃)₂ C(O)OH OCH(CH₃)₂ H H H DHP-449 C₁₀H₂₁ B CH₃ C(O)OCH₃ C(O)OH OCH₂CH₃ H H H DHP-450 C₁₀H₂₁ B CH₃ C(O)OCH₂CH₃ C(O)OH OCH₂CH₃ H H H DHP-451 C₁₀H₂₁ B CH₃ C(O)OCH(CH₃)₂ C(O)OH OCH₂CH₃ H H H DHP-452 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH₃ NO₂ NO₂ H DHP-453 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₃ OCH₃ NO₂ NO₂ H DHP-454 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH(CH₃)₂ OCH₃ NO₂ NO₂ H DHP-455 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH(CH₃)₂ NO₂ NO₂ H DHP-456 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₃ OCH(CH₃)₂ NO₂ NO₂ H DHP-457 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH(CH₃)₂ OCH(CH₃)₂ NO₂ NO₂ H DHP-458 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH₂CH₃ NO₂ NO₂ H DHP-459 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₃ OCH₂CH₃ NO₂ NO₂ H DHP-460 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH(CH₃)₂ OCH₂CH₃ NO₂ NO₂ H DHP-461 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH₃ OCH₃ NO₂ NO₂ H DHP-462 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH₂CH₃ OCH₃ NO₂ NO₂ H DHP-463 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH(CH₃)₂ OCH₃ NO₂ NO₂ H DHP-464 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH₃ OCH(CH₃)₂ NO₂ NO₂ H DHP-465 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH₂CH₃ OCH(CH₃)₂ NO₂ NO₂ H DHP-466 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH(CH₃)₂ OCH(CH₃)₂ NO₂ NO₂ H DHP-467 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH₃ OCH₂CH₃ NO₂ NO₂ H DHP-468 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH₂CH₃ OCH₂CH₃ NO₂ NO₂ H DHP-469 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH(CH₃)₂ OCH₂CH₃ NO₂ NO₂ H DHP-470 C₁₀H₂₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH(CH₃)₂ OCH₃ NO₂ NO₂ H DHP-471 C₁₀H₂₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₃ OCH₃ NO₂ NO₂ H DHP-472 C₁₀H₂₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₂CH₃ OCH₃ NO₂ NO₂ H DHP-473 C₁₀H₂₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH(CH₃)₂ OCH(CH₃)₂ NO₂ NO₂ H DHP-474 C₁₀H₂₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₃ OCH(CH₃)₂ NO₂ NO₂ H DHP-475 C₁₀H₂₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₂CH₃ OCH(CH₃)₂ NO₂ NO₂ H DHP-476 C₁₀H₂₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH(CH₃)₂ OCH₂CH₃ NO₂ NO₂ H DHP-477 C₁₀H₂₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₃ OCH₂CH₃ NO₂ NO₂ H DHP-478 C₁₀H₂₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₂CH₃ OCH₂CH₃ NO₂ NO₂ H DHP-479 C₁₀H₂₁ CH₃ CH₃ C(O)OH C(O)OH OCH₃ NO₂ NO₂ H DHP-480 C₁₀H₂₁ CH₃ CH₃ C(O)OH C(O)OCH₃ OCH₃ NO₂ NO₂ H DHP-481 C₁₀H₂₁ CH₃ CH₃ C(O)OH C(O)OCH₂CH₃ OCH₃ NO₂ NO₂ H DHP-482 C₁₀H₂₁ CH₃ CH₃ C(O)OH C(O)OCH(CH₃)₂ OCH₃ NO₂ NO₂ H DHP-483 C₁₀H₂₁ CH₃ CH₃ C(O)OH C(O)OH OCH(CH₃)₂ NO₂ NO₂ H DHP-484 C₁₀H₂₁ CH₃ CH₃ C(O)OH C(O)OCH₃ OCH(CH₃)₂ NO₂ NO₂ H DHP-485 C₁₀H₂₁ CH₃ CH₃ C(O)OH C(O)OCH₂CH₃ OCH(CH₃)₂ NO₂ NO₂ H DHP-486 C₁₀H₂₁ CH₃ CH₃ C(O)OH C(O)OCH(CH₃)₂ OCH(CH₃)₂ NO₂ NO₂ H DHP-487 C₁₀H₂₁ CH₃ CH₃ C(O)OH C(O)OH OCH₂CH₃ NO₂ NO₂ H DHP-488 C₁₀H₂₁ CH₃ CH₃ C(O)OH C(O)OCH₃ OCH₂CH₃ NO₂ NO₂ H DHP-489 C₁₀H₂₁ CH₃ CH₃ C(O)OH C(O)OCH₂CH₃ OCH₂CH₃ NO₂ NO₂ H DHP-490 C₁₀H₂₁ CH₃ CH₃ C(O)OH C(O)OCH(CH₃)₂ OCH₂CH₃ NO₂ NO₂ H DHP-491 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₃ C(O)OH OCH₃ NO₂ NO₂ H DHP-492 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OH OCH₃ NO₂ NO₂ H DHP-493 C₁₀H₂₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OH OCH₃ NO₂ NO₂ H DHP-494 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₃ C(O)OH OCH(CH₃)₂ NO₂ NO₂ H DHP-495 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OH OCH(CH₃)₂ NO₂ NO₂ H DHP-496 C₁₀H₂₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OH OCH(CH₃)₂ NO₂ NO₂ H DHP-497 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₃ C(O)OH OCH₂CH₃ NO₂ NO₂ H DHP-498 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OH OCH₂CH₃ NO₂ NO₂ H DHP-499 C₁₀H₂₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OH OCH₂CH₃ NO₂ NO₂ H DHP-500 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH₃ NO₂ H H DHP-501 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₃ OCH₃ NO₂ H H DHP-502 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH(CH₃)₂ OCH₃ NO₂ H H DHP-503 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH(CH₃)₂ NO₂ H H DHP-504 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₃ OCH(CH₃)₂ NO₂ H H DHP-505 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH(CH₃)₂ OCH(CH₃)₂ NO₂ H H DHP-506 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH₂CH₃ NO₂ H H DHP-507 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₃ OCH₂CH₃ NO₂ H H DHP-508 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH(CH₃)₂ OCH₂CH₃ NO₂ H H DHP-509 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH₃ OCH₃ NO₂ H H DHP-510 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH₂CH₃ OCH₃ NO₂ H H DHP-511 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH(CH₃)₂ OCH₃ NO₂ H H DHP-512 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH₃ OCH(CH₃)₂ NO₂ H H DHP-513 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH₂CH₃ OCH(CH₃)₂ NO₂ H H DHP-514 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH(CH₃)₂ OCH(CH₃)₂ NO₂ H H DHP-515 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH₃ OCH₂CH₃ NO₂ H H DHP-516 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH₂CH₃ OCH₂CH₃ NO₂ H H DHP-517 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH(CH₃)₂ OCH₂CH₃ NO₂ H H DHP-518 C₁₀H₂₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH(CH₃)₂ OCH₃ NO₂ H H DHP-519 C₁₀H₂₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₃ OCH₃ NO₂ H H DHP-520 C₁₀H₂₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₂CH₃ OCH₃ NO₂ H H DHP-521 C₁₀H₂₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH(CH₃)₂ OCH(CH₃)₂ NO₂ H H DHP-522 C₁₀H₂₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₃ OCH(CH₃)₂ NO₂ H H DHP-523 C₁₀H₂₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₂CH₃ OCH(CH₃)₂ NO₂ H H DHP-524 C₁₀H₂₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH(CH₃)₂ OCH₂CH₃ NO₂ H H DHP-525 C₁₀H₂₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₃ OCH₂CH₃ NO₂ H H DHP-526 C₁₀H₂₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₂CH₃ OCH₂CH₃ NO₂ H H DHP-527 C₁₀H₂₁ CH₃ CH₃ C(O)OH C(O)OH OCH₃ NO₂ H H DHP-528 C₁₀H₂₁ CH₃ CH₃ C(O)OH C(O)OCH₃ OCH₃ NO₂ H H DHP-529 C₁₀H₂₁ CH₃ CH₃ C(O)OH C(O)OCH₂CH₃ OCH₃ NO₂ H H DHP-530 C₁₀H₂₁ CH₃ CH₃ C(O)OH C(O)OCH(CH₃)₂ OCH₃ NO₂ H H DHP-531 C₁₀H₂₁ CH₃ CH₃ C(O)OH C(O)OH OCH(CH₃)₂ NO₂ H H DHP-532 C₁₀H₂₁ CH₃ CH₃ C(O)OH C(O)OCH₃ OCH(CH₃)₂ NO₂ H H DHP-533 C₁₀H₂₁ CH₃ CH₃ C(O)OH C(O)OCH₂CH₃ OCH(CH₃)₂ NO₂ H H DHP-534 C₁₀H₂₁ CH₃ CH₃ C(O)OH C(O)OCH(CH₃)₂ OCH(CH₃)₂ NO₂ H H DHP-535 C₁₀H₂₁ CH₃ CH₃ C(O)OH C(O)OH OCH₂CH₃ NO₂ H H DHP-536 C₁₀H₂₁ CH₃ CH₃ C(O)OH C(O)OCH₃ OCH₂CH₃ NO₂ H H DHP-537 C₁₀H₂₁ CH₃ CH₃ C(O)OH C(O)OCH₂CH₃ OCH₂CH₃ NO₂ H H DHP-538 C₁₀H₂₁ CH₃ CH₃ C(O)OH C(O)OCH(CH₃)₂ OCH₂CH₃ NO₂ H H DHP-539 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₃ C(O)OH OCH₃ NO₂ H H DHP-540 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OH OCH₃ NO₂ H H DHP-541 C₁₀H₂₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OH OCH₃ NO₂ H H DHP-542 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₃ C(O)OH OCH(CH₃)₂ NO₂ H H DHP-543 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OH OCH(CH₃)₂ NO₂ H H DHP-544 C₁₀H₂₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OH OCH(CH₃)₂ NO₂ H H DHP-545 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₃ C(O)OH OCH₂CH₃ NO₂ H H DHP-546 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OH OCH₂CH₃ NO₂ H H DHP-547 C₁₀H₂₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OH OCH₂CH₃ NO₂ H H DHP-548 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH₃ H NO₂ H DHP-549 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₃ OCH₃ H NO₂ H DHP-550 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH(CH₃)₂ OCH₃ H NO₂ H DHP-551 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH(CH₃)₂ H NO₂ H DHP-552 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₃ OCH(CH₃)₂ H NO₂ H DHP-553 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH(CH₃)₂ OCH(CH₃)₂ H NO₂ H DHP-554 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH₂CH₃ H NO₂ H DHP-555 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₃ OCH₂CH₃ H NO₂ H DHP-556 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH(CH₃)₂ OCH₂CH₃ H NO₂ H DHP-557 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH₃ OCH₃ H NO₂ H DHP-558 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH₂CH₃ OCH₃ H NO₂ H DHP-559 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH(CH₃)₂ OCH₃ H NO₂ H DHP-560 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH₃ OCH(CH₃)₂ H NO₂ H DHP-561 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH₂CH₃ OCH(CH₃)₂ H NO₂ H DHP-562 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH(CH₃)₂ OCH(CH₃)₂ H NO₂ H DHP-563 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH₃ OCH₂CH₃ H NO₂ H DHP-564 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH₂CH₃ OCH₂CH₃ H NO₂ H DHP-565 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₃ C(O)OCH(CH₃)₂ OCH₂CH₃ H NO₂ H DHP-566 C₁₀H₂₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH(CH₃)₂ OCH₃ H NO₂ H DHP-567 C₁₀H₂₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₃ OCH₃ H NO₂ H DHP-568 C₁₀H₂₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₂CH₃ OCH₃ H NO₂ H DHP-569 C₁₀H₂₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH(CH₃)₂ OCH(CH₃)₂ H NO₂ H DHP-570 C₁₀H₂₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₃ OCH(CH₃)₂ H NO₂ H DHP-571 C₁₀H₂₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₂CH₃ OCH(CH₃)₂ H NO₂ H DHP-572 C₁₀H₂₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH(CH₃)₂ OCH₂CH₃ H NO₂ H DHP-573 C₁₀H₂₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₃ OCH₂CH₃ H NO₂ H DHP-574 C₁₀H₂₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OCH₂CH₃ OCH₂CH₃ H NO₂ H DHP-575 C₁₀H₂₁ CH₃ CH₃ C(O)OH C(O)OH OCH₃ H NO₂ H DHP-576 C₁₀H₂₁ CH₃ CH₃ C(O)OH C(O)OCH₃ OCH₃ H NO₂ H DHP-577 C₁₀H₂₁ CH₃ CH₃ C(O)OH C(O)OCH₂CH₃ OCH₃ H NO₂ H DHP-578 C₁₀H₂₁ CH₃ CH₃ C(O)OH C(O)OCH(CH₃)₂ OCH₃ H NO₂ H DHP-579 C₁₀H₂₁ CH₃ CH₃ C(O)OH C(O)OH OCH(CH₃)₂ H NO₂ H DHP-580 C₁₀H₂₁ CH₃ CH₃ C(O)OH C(O)OCH₃ OCH(CH₃)₂ H NO₂ H DHP-581 C₁₀H₂₁ CH₃ CH₃ C(O)OH C(O)OCH₂CH₃ OCH(CH₃)₂ H NO₂ H DHP-582 C₁₀H₂₁ CH₃ CH₃ C(O)OH C(O)OCH(CH₃)₂ OCH(CH₃)₂ H NO₂ H DHP-583 C₁₀H₂₁ CH₃ CH₃ C(O)OH C(O)OH OCH₂CH₃ H NO₂ H DHP-584 C₁₀H₂₁ CH₃ CH₃ C(O)OH C(O)OCH₃ OCH₂CH₃ H NO₂ H DHP-585 C₁₀H₂₁ CH₃ CH₃ C(O)OH C(O)OCH₂CH₃ OCH₂CH₃ H NO₂ H DHP-586 C₁₀H₂₁ CH₃ CH₃ C(O)OH C(O)OCH(CH₃)₂ OCH₂CH₃ H NO₂ H DHP-587 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₃ C(O)OH OCH₃ H NO₂ H DHP-588 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OH OCH₃ H NO₂ H DHP-589 C₁₀H₂₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OH OCH₃ H NO₂ H DHP-590 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₃ C(O)OH OCH(CH₃)₂ H NO₂ H DHP-591 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OH OCH(CH₃)₂ H NO₂ H DHP-592 C₁₀H₂₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OH OCH(CH₃)₂ H NO₂ H DHP-593 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₃ C(O)OH OCH₂CH₃ H NO₂ H DHP-594 C₁₀H₂₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OH OCH₂CH₃ H NO₂ H DHP-595 C₁₀H₂₁ CH₃ CH₃ C(O)OCH(CH₃)₂ C(O)OH OCH₂CH₃ H NO₂ H DHP-596 C₁₀H₂₁ CH₃ C# C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH₃ H H H DHP-597 C₁₀H₂₁ CH₃ C C(O)OCH₂CH₃ C(O)OCH₃ OCH₃ H H H DHP-598 C₁₀H₂₁ CH₃ C C(O)OCH₂CH₃ C(O)OCH(CH₃)₂ OCH₃ H H H DHP-599 C₁₀H₂₁ CH₃ C C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH(CH₃)₂ H H H DHP-600 C₁₀H₂₁ CH₃ C C(O)OCH₂CH₃ C(O)OCH₃ OCH(CH₃)₂ H H H DHP-601 C₁₀H₂₁ CH₃ C C(O)OCH₂CH₃ C(O)OCH(CH₃)₂ OCH(CH₃)₂ H H H DHP-602 C₁₀H₂₁ CH₃ C C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH₂CH₃ H H H DHP-603 C₁₀H₂₁ CH₃ C C(O)OCH₂CH₃ C(O)OCH₃ OCH₂CH₃ H H H DHP-604 C₁₀H₂₁ CH₃ C C(O)OCH₂CH₃ C(O)OCH(CH₃)₂ OCH₂CH₃ H H H DHP-605 C₁₀H₂₁ CH₃ C C(O)OCH₃ C(O)OCH₃ OCH₃ H H H DHP-606 C₁₀H₂₁ CH₃ C C(O)OCH₃ C(O)OCH₂CH₃ OCH₃ H H H DHP-607 C₁₀H₂₁ CH₃ C C(O)OCH₃ C(O)OCH(CH₃)₂ OCH₃ H H H DHP-608 C₁₀H₂₁ CH₃ C C(O)OCH₃ C(O)OCH₃ OCH(CH₃)₂ H H H DHP-609 C₁₀H₂₁ CH₃ C C(O)OCH₃ C(O)OCH₂CH₃ OCH(CH₃)₂ H H H DHP-610 C₁₀H₂₁ CH₃ C C(O)OCH₃ C(O)OCH(CH₃)₂ OCH(CH₃)₂ H H H DHP-611 C₁₀H₂₁ CH₃ C C(O)OCH₃ C(O)OCH₃ OCH₂CH₃ H H H DHP-612 C₁₀H₂₁ CH₃ C C(O)OCH₃ C(O)OCH₂CH₃ OCH₂CH₃ H H H DHP-613 C₁₀H₂₁ CH₃ C C(O)OCH₃ C(O)OCH(CH₃)₂ OCH₂CH₃ H H H DHP-614 C₁₀H₂₁ CH₃ C C(O)OCH(CH₃)₂ C(O)OCH(CH₃)₂ OCH₃ H H H DHP-615 C₁₀H₂₁ CH₃ C C(O)OCH(CH₃)₂ C(O)OCH₃ OCH₃ H H H DHP-616 C₁₀H₂₁ CH₃ C C(O)OCH(CH₃)₂ C(O)OCH₂CH₃ OCH₃ H H H DHP-617 C₁₀H₂₁ CH₃ C C(O)OCH(CH₃)₂ C(O)OCH(CH₃)₂ OCH(CH₃)₂ H H H DHP-618 C₁₀H₂₁ CH₃ C C(O)OCH(CH₃)₂ C(O)OCH₃ OCH(CH₃)₂ H H H DHP-619 C₁₀H₂₁ CH₃ C C(O)OCH(CH₃)₂ C(O)OCH₂CH₃ OCH(CH₃)₂ H H H DHP-620 C₁₀H₂₁ CH₃ C C(O)OCH(CH₃)₂ C(O)OCH(CH₃)₂ OCH₂CH₃ H H H DHP-621 C₁₀H₂₁ CH₃ C C(O)OCH(CH₃)₂ C(O)OCH₃ OCH₂CH₃ H H H DHP-622 C₁₀H₂₁ CH₃ C C(O)OCH(CH₃)₂ C(O)OCH₂CH₃ OCH₂CH₃ H H H DHP-623 C₁₀H₂₁ CH₃ C C(O)OH C(O)OH OCH₃ H H H DHP-624 C₁₀H₂₁ CH₃ C C(O)OH C(O)OCH₃ OCH₃ H H H DHP-625 C₁₀H₂₁ CH₃ C C(O)OH C(O)OCH₂CH₃ OCH₃ H H H DHP-626 C₁₀H₂₁ CH₃ C C(O)OH C(O)OCH(CH₃)₂ OCH₃ H H H DHP-627 C₁₀H₂₁ CH₃ C C(O)OH C(O)OH OCH(CH₃)₂ H H H DHP-628 C₁₀H₂₁ CH₃ C C(O)OH C(O)OCH₃ OCH(CH₃)₂ H H H DHP-629 C₁₀H₂₁ CH₃ C C(O)OH C(O)OCH₂CH₃ OCH(CH₃)₂ H H H DHP-630 C₁₀H₂₁ CH₃ C C(O)OH C(O)OCH(CH₃)₂ OCH(CH₃)₂ H H H DHP-631 C₁₀H₂₁ CH₃ C C(O)OH C(O)OH OCH₂CH₃ H H H DHP-632 C₁₀H₂₁ CH₃ C C(O)OH C(O)OCH₃ OCH₂CH₃ H H H DHP-633 C₁₀H₂₁ CH₃ C C(O)OH C(O)OCH₂CH₃ OCH₂CH₃ H H H DHP-634 C₁₀H₂₁ CH₃ C C(O)OH C(O)OCH(CH₃)₂ OCH₂CH₃ H H H DHP-635 C₁₀H₂₁ CH₃ C C(O)OCH₃ C(O)OH OCH₃ H H H DHP-636 C₁₀H₂₁ CH₃ C C(O)OCH₂CH₃ C(O)OH OCH₃ H H H DHP-637 C₁₀H₂₁ CH₃ C C(O)OCH(CH₃)₂ C(O)OH OCH₃ H H H DHP-638 C₁₀H₂₁ CH₃ C C(O)OCH₃ C(O)OH OCH(CH₃)₂ H H H DHP-639 C₁₀H₂₁ CH₃ C C(O)OCH₂CH₃ C(O)OH OCH(CH₃)₂ H H H DHP-640 C₁₀H₂₁ CH₃ C C(O)OCH(CH₃)₂ C(O)OH OCH(CH₃)₂ H H H DHP-641 C₁₀H₂₁ CH₃ C C(O)OCH₃ C(O)OH OCH₂CH₃ H H H DHP-642 C₁₀H₂₁ CH₃ C C(O)OCH₂CH₃ C(O)OH OCH₂CH₃ H H H DHP-643 C₁₀H₂₁ CH₃ C C(O)OCH(CH₃)₂ C(O)OH OCH₂CH₃ H H H DHP-644 C₁₀H₂₁ CH₃ CH₃ CH₂OCH₃ CH₂OCH₃ OCH₃ H H H DHP-645 C₁₀H₂₁ CH₃ CH₃ CH₂OCH₃ CH₂OCH₂CH₃ OCH₃ H H H DHP-646 C₁₀H₂₁ CH₃ CH₃ CH₂OCH₃ CH₂OCH(CH₃)₂ OCH₃ H H H DHP-647 C₁₀H₂₁ CH₃ CH₃ CH₂OCH₂CH₃ CH₂OCH₃ OCH(CH₃)₂ H H H DHP-648 C₁₀H₂₁ CH₃ CH₃ CH₂OCH₂CH₃ CH₂OCH₂CH₃ OCH(CH₃)₂ H H H DHP-649 C₁₀H₂₁ CH₃ CH₃ CH₂OCH₂CH₃ CH₂OCH(CH₃)₂ OCH(CH₃)₂ H H H DHP-650 C₁₀H₂₁ CH₃ CH₃ CH₂OCH(CH₃)₂ CH₂OCH₃ OCH₂CH₃ H H H DHP-651 C₁₀H₂₁ CH₃ CH₃ CH₂OCH(CH₃)₂ CH₂OCH₂CH₃ OCH₂CH₃ H H H DHP-652 C₁₀H₂₁ CH₃ CH₃ CH₂OCH(CH₃)₂ CH₂OCH(CH₃)₂ OCH₂CH₃ H H H DHP-653 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₂OCH₃ C(O)OCH₂CH₃ OCH₂CH₃ H H H DHP-654 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH₂CH₂OCH₃ H H H DHP-655 C₁₅H₃₁ CH₃ CH₃ C(O)OCH₂CH₃ C(O)OCH₂CH₃ OCH₂CH₃ H NH₂ H In all of the above compounds, R₁₀ = R₁₁ = H. *: A =

**: B = —CH₂—O—CH₂CH₂NH₂ #: C =

Also contemplated as part of the present invention are four other series of compounds resembling those in Table 1. These series are designated by the suffixes -11, -12, -13, and -14. They are identical to DHP-1 through DHP-326 and DHP-653 through DHP-655, except that in each of the -11 series compounds R₁ is C₁₁H₂₃; in each of the -12 series compounds R₁ is C₁₂H₂₅; in each of the -13 series compounds RI is C₁₃H₂₇; and in each of the -14 series compounds R₁ is C₁₄H₂₉. Thus, the inventors specifically contemplate each of DHP-1-11 through DHP-326-11 and DHP-653-11 through DHP-655-11; DHP-1-12 through DHP-326-12 and DHP-653-12 through DHP-655-12; DHP-1-13 through DHP-326-13 and DHP-653-13 through DHP-655-13; and DHP-1-14 through DHP-326-14 and DHP-653-14 through DHP-655-14, as explicitly as if the exact formula of each was set forth herein individually.

II. Methods of Treatment

In another aspect, the invention relates to a method of modulating the activity of a calcium channel in a cell comprising the step of contacting said cell with a compound of Formula I, as described above. The calcium channel being modulated may be a low voltage activated calcium channel or a high voltage activated calcium channel.

In a further aspect, the invention relates to a method of treating a disease associated with a cellular calcium channel comprising identifying a subject in need of such treatment, and administering to the subject a therapeutically effective amount of a compound of Formula I, as described above. In certain embodiments, the subject may be a mammal. The mammal may be selected from the group consisting of mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, primates, such as monkeys, chimpanzees, and apes, and humans. In some embodiments, the subject is a human. Embodiments of the invention include those in which the disease to be treated is a cardiovascular disease or a neurological disorder.

III. Pharmaceutical Compositions

In another aspect, the invention relates to a pharmaceutical composition comprising a compound of Formula I or II, as described above, and a physiologically acceptable carrier, diluent, or excipient, or a combination thereof.

The term “pharmaceutical composition” refers to a mixture of a compound of the invention with other chemical components, such as carriers, diluents or excipients. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to: intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary and topical administration. Pharmaceutical compositions can also be obtained by reacting compounds with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.

The term “carrier” defines a nontoxic chemical compound that facilitates the incorporation of a compound into cells or tissues. For example, human serum albumin (HSA) is a commonly utilized carrier as it facilitates the uptake of many organic compounds into the cells or tissues of an organism.

The term “diluent” defines chemical compounds that are used to dilute the compound of interest prior to delivery. Diluents can also be used to stabilize compounds because they can provide a more stable environment. Salts dissolved in buffered solutions (providing pH control) are utilized as diluents in the art. One commonly used buffered solution is phosphate buffered saline. It is a buffer found naturally in the blood system. Since buffer salts can control the pH of a solution at low concentrations, a buffered diluent rarely modifies the biological activity of a compound.

The term “physiologically acceptable” defines a carrier or diluent that does not abrogate the biological activity or properties of the compound, and is nontoxic.

The compounds described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or suitable carriers or excipient(s). Techniques for formulation and administration of the compounds of the instant application may be found in “Remington's Pharmaceutical Sciences,” 20th ed. Edited by Alfonso Gennaro, 2000.

a) Routes of Administration

Suitable routes of administration may, for example, include oral, rectal, transmucosal, pulmonary, ophthalmic or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injections.

Alternately, one may administer the compound in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot or sustained release formulation. Furthermore, one may administer the drug in a targeted drug delivery system, for example, in a liposome coated with organ-specific antibody. The liposomes will be targeted to and taken up selectively by the organ.

b) Composition/Formulation

The pharmaceutical compositions of the present invention may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.

Pharmaceutical compositions for use in accordance with the present invention thus may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g., in Remington's Pharmaceutical Sciences, above.

For intravenous injections, the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. For other parenteral injections, the agents of the invention may be formulated in aqueous or nonaqueous solutions, preferably with physiologically compatible buffers or excipients. Such excipients are generally known in the art.

For oral administration, the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers or excipients well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipient with one or more compound of the invention, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as: for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethyl cellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrating agents may be added, such as the cross-linked croscarmellose sodium, polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.

For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, or gels formulated in conventional manner.

For administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

The compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.

Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

A pharmaceutical carrier for the hydrophobic compounds of the invention is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. The cosolvent system may be a 10% ethanol, 10% polyethylene glycol 300, 10% polyethylene glycol 40 castor oil (PEG-40 castor oil) with 70% aqueous solution. This cosolvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration. Naturally, the proportions of a cosolvent system may be varied considerably without destroying its solubility and toxicity characteristics. Furthermore, the identity of the cosolvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of PEG-40 castor oil, the fraction size of polyethylene glycol 300 may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides maybe included in the aqueous solution.

Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as N-methylpyrrolidone also may be employed, although usually at the cost of greater toxicity. Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.

Many of the compounds of the invention may be provided as salts with pharmaceutically compatible counterions. Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free acid or base forms.

c) Effective Dosage

Pharmaceutical compositions suitable for use in the present invention include compositions where the active ingredients are contained in an amount effective to achieve its intended purpose. More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.

For any compound used in the methods of the invention, the therapeutically effective dose can be estimated initially from cell culture assays. For example, a dose can be formulated in animal models to achieve a circulating concentration range that includes the IC₅₀ as determined in cell culture. Such information can be used to more accurately determine useful doses in humans.

Toxicity and therapeutic efficacy of the compounds described herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD₅₀ (the dose lethal to 50% of the population) and the ED₅₀ (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD₅₀ and ED₅₀. Compounds which exhibit high therapeutic indices are preferred. The data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED₅₀ with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. (See e.g., Fingl et al. 1975, in “The Pharmacological Basis of Therapeutics”, Ch. 1 p. 1). Typically, the dose range of the composition administered to the patient can be from about 0.5 to 1000 mg/kg of the patient's body weight. The dosage may be a single one or a series of two or more given in the course of one or more days, as is needed by the patient.

The daily dosage regimen for an adult human patient may be, for example, an oral dose of between 0.1 mg and 500 mg, preferably between 1 mg and 250 mg, e.g. 5 to 200 mg or an intravenous, subcutaneous, or intramuscular dose of between 0.01 mg and 100 mg, preferably between 0.1 mg and 60 mg, e.g. 1 to 40 mg of the compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day. Alternatively the compounds of the invention may be administered by continuous intravenous infusion, preferably at a dose of up to 400 mg per day. Thus, the total daily dosage by oral administration will be in the range 1 to 2000 mg and the total daily dosage by parenteral administration will be in the range 0.1 to 400 mg. Suitably the compounds will be administered for a period of continuous therapy, for example for a week or more.

Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vitro data; e.g., the concentration necessary to achieve 50-90% of calcium channel blockage, using the assays known in the art. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations.

Dosage intervals can also be determined using MEC value. Compounds should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%.

In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.

The amount of composition administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.

d) Packaging

The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

IV. Synthesis of the Compounds of the Invention

Some of the compounds of the present invention can be synthesized using the general synthetic procedures set forth below, in Schemes 1-12.

Reagents: (i) R₂SO₄/K₂CO₃, acetone, reflux 3 h; (ii) H₂O₂, HCOOH; (iii) NaIO₄, THF-water, 5° C., 2 h; (iv) R₁CH═PPh₃, potassium-t-butoxide, dichloromethane, 12 h; (v) Pd/C, H₂, methanol, 3 h; (vi) LiAlH₄, tetrahydrofuran, reflux, 3 h; (vii) PCC, dichloromethane, rt. 3 h; (viii) CH₃COCH₂COOR₂/piperidine, acetic acid, n-butanol, rt. 3 h; (ix) (CH₃)(NH₂)C═CH(COOR₃), n-butanol, reflux, 10 h.

Reagents: (i) R₂SO₄/K₂CO₃, acetone, reflux 3 h; (ii) LiAlH₄, tetrahydrofuran, reflux, 3 h; (iii) PCC, dichloromethane, rt. 3 h; (iv) CH₃COCH₂COOR₁/piperidine, acetic acid, n-butanol, rt. 3 h; (v) (CH₃)(NH₂)C═CH(COOR₂), n-butanol, reflux, 10 h.

Reagents: (i) H₂SO₄/HNO₃, 5° C., 2 h; (ii) R₂SO₄/K₂CO₃, acetone, reflux 3 h; (iii) LiAlH₄, tetrahydrofuran, reflux, 3 h; (iv) PCC, dichloromethane, rt. 3 h; (v) CH₃COCH₂COOR₁/piperidine, acetic acid, n-butanol, rt. 3 h; (vi) (CH₃)(NH₂)C═CH(COOR₂), n-butanol, reflux, 10 h.

Reagents: (i) H₂SO₄/HNO₃, 5° C., 2 h; (ii) R₂SO₄/K₂CO₃, acetone, reflux 3 h; (iii) LiAlH₄, tetrahydrofuran, reflux, 3 h; (iv) PCC, dichloromethane, rt. 3 h; (v) CH₃COCH₂COOR₁/piperidine, acetic acid, n-butanol, rt. 3 h; (vi) (CH₃)(NH₂)C═CH(COOR₂), n-butanol, reflux, 10 h; (vii) Sn, Conc. HCl.

Reagents: (i) H₂SO₄/HNO₃, 5° C., 2 h; (ii) R₂SO₄/K₂CO₃, acetone, reflux 3 h; (iii) LiAlH₄, tetrahydrofuran, reflux, 3 h; (iv) PCC, dichloromethane, rt. 3 h; (v) CH₃COCH₂COOR₁/piperidine, acetic acid, n-butanol, rt. 3 h; (vi) (CH₃)(NH₂)C═CH(COOR₂), n-butanol, reflux, 10 h; (vii) Sn, Conc. HCl; (viii) NaNO₂/Conc. HCl, 2 h; (ix) Cu(I)CN, dichloromethane, 3 h.

Reagents: (i) H₂SO₄/HNO₃, 5° C., 2 h; (ii) R₂SO₄/K₂CO₃, acetone, reflux 3 h; (iii) LiAlH₄, tetrahydrofuran, reflux, 3 h; (iv) PCC, dichloromethane, rt. 3 h; (v) CH₃COCH₂COOR₁/piperidine, acetic acid, n-butanol, rt. 3 h; (vi) (CH₃)(NH₂)C═CH(COOR₂), n-butanol, reflux, 10 h; (vii) Sn, Conc. HCl; (viii) NaNO₂/Conc. HCl, 2 h; (ix) H₂O 30 min.

Reagents: (i) R₂SO₄/K₂CO₃, acetone, reflux 3 h; (ii) LiAlH₄, tetrahydrofuran, reflux, 3 h; (iii) PCC, dichloromethane, rt. 3 h; (iv) CH₃COCH₂COOR₁/piperidine, acetic acid, n-butanol, rt. 3 h; (v) (CH₃)(NH₂)C═CH(COOR₂), n-butanol, reflux, 10 h; (vi) NaOH, methanol, reflux, 4 h.

Reagents: (i) H₂SO₄/HNO₃, 5° C., 2 h; (ii) R₂SO₄/K₂CO₃, acetone, reflux 3 h; (iii) LiAlH₄, tetrahydrofuran, reflux, 3 h; (iv) PCC, dichloromethane, rt. 3 h; (v) CH₃COCH₂COOR₁/piperidine, acetic acid, n-butanol, rt. 3 h; (vi) (CH₃)(NH₂)C═CH(COOR₂), n-butanol, reflux, 10 h; (vii) Sn, Conc. HCl; (viii) NaNO₂/Conc. HCl, 2 h; (ix) SbF₆, dichloromethane, 3 h.

Reagents: (i) R₂SO₄/K₂CO₃, acetone, reflux 3 h; (ii) LiAlH₄, tetrahydrofuran, reflux, 3 h; (iii) PCC, dichloromethane, rt. 3 h; (iv) CH₃COCH₂C(S)OR₁/piperidine, acetic acid, n-butanol, rt. 3 h; (v) (CH₃)(NH₂)C═CH(COOR₂), n-butanol, reflux, 10 h.

Reagents: (i) R₂SO₄/K₂CO₃, acetone, reflux 3 h; (ii) LiAlH₄, tetrahydrofuran, reflux, 3 h; (iii) PCC, dichloromethane, rt. 3 h; (iv) CH₃COCH₂C(O)SR₁/piperidine, acetic acid, n-butanol, rt. 3 h; (v) (CH₃)(NH₂)C═CH(COOR₂), n-butanol, reflux, 10 h.

Reagents: (i) R₂SO₄/K₂CO₃, acetone, reflux 3 h; (ii) LiAlH₄, tetrahydrofuran, reflux, 3 h; (iii) PCC, dichloromethane, rt. 3 h; (iv) CH₃COCH₂CH_(2 0R) ₁/piperidine, acetic acid, n-butanol, rt. 3 h; (v) (CH₃)(NH₂)C═CH(CH₂OR₂), n-butanol, reflux, 10 h.

Reagents: (i) 2 C₁₀H₂₁Li, THF, 3 h; (ii) CO₂, 4 h; (iii) HVP, dichloromethane, reflux, 6 h; (iv) R₂SO₄/K₂CO₃, acetone, reflux 3 h; (v) LiAlH₄, tetrahydrofuran, reflux, 3 h; (vi) PCC, dichloromethane, rt. 3 h; (vii) CH₃COCH₂COOR₁/piperidine, acetic acid, n-butanol, rt. 3 h; (viii) (CH₃)(NH₂)C═CH(COOR₂), n-butanol, reflux, 10 h.

Certain of the compounds of the general Formula I or II were prepared by the well-known Hantzsch dihydropyridine synthesis. In this method appropriate aldehyde was condensed with an appropriate beta keto esters like methyl acetoacetate, ethyl acetoacetate, isopropyl acetoacetate, ethyl 4-chloro acetoacetate and like, in inert solvent such as methanol, ethanol, isopropyl alcohol, n-butanol, an ether solvent such as 1,2-dimethoxyethane or tetrahydrofuran (THF), an amide solvent such as dimethyl formamide (DMF) or N-methylpyrrolidone, a sulfoxide solvent such as dimethyl sulfoxide (DMSO) or sulfolane, an aromatic hydrocarbon solvent such as benzene, toluene or xylene in presence of piperidine and acetic acid. If required, the knoevenegal product was purified by column chromatography and reacted with appropriate amino crotonate like methyl-3-amino crotonate, ethyl 3-amino crotonate, isopropyl 3-amino crotonate. The reaction is usually conducted at temperature from room temperature to 200° C., preferably from 60 to 140° C., for from 1-100 hours, preferably from 6 to 40 hours. The corresponding Hantzsch product was purified by column chromatography using silicagel (100-200 mesh) and/or crystallised using appropriate organic solvents like hexane, petroleum ether (40-60° C.), ethanol etc. Substrates like 2-mercapto benzimidazole, (5-methyl)2-mercapto benzimidazole, 2-amino ethanol and like as mentioned in claim 1 were used for substitutions on dihydropyridine ring.

For the processes mentioned above, any desired ratio of the substances participating in the reaction can be used. In general, however, the process is carried out with molar amounts of the reactants.

The synthesis of compounds includes enantiomerically pure forms obtained by methods such as, by separating diastereomer mixtures of the compounds of the general Formula I or II, from an enantiomerically pure chiral alcohol, by a customary method, subsequently preparing the enantiomerically pure carboxylic acids and/or any methods used for separation of enantiomers, for example, methods discussed by S. Goldmann and J. Stoltefuss [S. Goldmann and J. Stoltefuss “1,4-Dihydropyridine: Effects of chirality and conformation on the calcium antagonist and calcium agonist activities” Angewandte Chemie International Edition (English) 30, 1559-1578 (1991)].

As indicated above, the compounds and compositions of this invention are useful as calcium entry blockers, and thus have broad pharmacological utility in that they exhibit (i) pronounced and long-lasting vasodilating effect accompanied by an energy-sparing effect on cardiac metabolism; (ii) antiarrythmic and antianginal action on cardiac muscle; (iii) vascular spasmolytic action; (iv) antihypertensive action; (v) spasmolytic action on the smooth muscle of the gastrointestinal and urogenital tracts and the cerebrovascular and respiratory systems; (vi) as antihypercholestorolemic and antilipidemic agents; (vii) protection of the ischemic myocardium; (viii) inhibit irritable bowel syndrome and esophagel spasm; (ix)inhibit migraine; and, (x) epilepsy. Some of are also useful cardiotonic agents. This list also includes any cardiovascular problems related to low voltage activated (LVA) and high voltage activated (HVA) calcium channels.

The representative compounds of the present invention might inhibit vascular calcium contraction, reduce cardiac contractile force, inhibit calcium mediated tracheal contraction, inhibit calcium uptake in pituitary cells, or displace tritiated nitrendipine from membrane.

EXAMPLES

The examples below are illustrative of some of the embodiments of the invention only and should not be construed to limit the scope of the claims.

Example 1 Extraction of ene Mixture of anacardic acid (2-hydroxy-6-pentadecyl benzoic acid) from Solvent Extracted CNSL

Commercially available solvent extracted cashew nut shell liquid (CNSL) (100 g) was dissolved in 5% aqueous methanol (600 mL). To the methanolic solution was added activated charcoal (20 g), stirred for 15 minutes, then filtered over celite bed to remove any insoluble material. The clear filtrate was transferred into three neck round bottom flask fitted with a double surface reflux condenser and mechanical stirrer. Calcium hydroxide (50 g) was added in portions at room temperature and the reaction mass temperature was raised to 50° C. and allowed to maintain for 3 hrs. Progress of the reaction was monitored by thin layer chromatography (TLC) using hexane-ethyl acetate (8:2) as mobile phase. After the completion of reaction, the precipitated calcium anacardate was filtered and washed thoroughly with methanol (200 mL). The resultant cake was dried under vacuum at 45-50° C. for 2 hrs to yield calcium anacardate (120 g).

Dry cake (120 g) was suspended in distilled water (440 mL), added concentrated hydrochloric acid (33%, 60 mL) and stirred for 1 hr. Resultant solution was extracted with ethylacetate (2×150 mL). The combined organic layer was washed with distilled water (2×500 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield an ene mixture of anacardic acid. (Yield: 60 g).

Example 2 Hydrogenation of anacardic acid ene Mixture

Anacardic acid ene mixture (30 g,) was dissolved in methanol (120 ml). 5% Pd/C (0.75 g, 2.5%) was added slowly and this solution were transferred to 250-mL hydrogenation flask. Initially the solution was flushed with nitrogen and then with hydrogen. Hydrogenation was carried out with 2.5 kg/cm² hydrogen gas pressure for 2 hrs. Then the solution was filtered through a celite bed to obtain catalyst free solution. This was evaporated under vacuum to get crude saturated anacardic acid. It was then recrystallised from petroleum ether (Yield: 25 g).

Example 3 Synthesis of ethyl 2-ethoxy-6-pentadecyl-benzoate

Anacardic acid (10.11 g, 29 mmol) was dissolved in acetone (60 mL) and potassium carbonate (4.0 g, 29 mmol) was charged. Diethyl sulfate (8.93 g, 58 mmol) was added slowly under stirring. This solution was then transferred to a three-neck flask fitted with a reflux condenser and mechanical stirrer, and refluxed for 4 hrs. Progress of reaction was monitored by TLC (mobile phase:Hexane:EtOAc 9:1). After completion of reaction, it was filtered and acetone was evaporated under vacuum. Crude product was dissolved in dichloromethane (50 mL) and washed with water (2×50 mL), 5% sodium bicarbonate solution (50 mL), saturated brine (50 mL) and finally with distilled water (2×50 mL). The organic layer was dried over anhydrous sodium sulphate, and evaporated under vacuum to give ethyl 2-ethoxy-6-pentadecyl-benzoate as oil. This was then dissolved in minimum amount of petroleum ether (40-60° C.) and cooled to 0° C. to give light brownish crystals (Yield: 12 g).

Example 4 Synthesis of isopropyl 2-isopropoxy-6-pentadecyl-benzoate

Anacardic acid (10.11 g, 29 mmol) was dissolved in isobutyl methyl ketone (60 mL). To this, finely powdered potassium carbonate (4.0 g, 29 mmol) and benzyl tributyl ammonium chloride (1 g) was added. Slowly, isopropyl bromide (7.13 g, 58 mmol) was added and refluxed for 8 hrs. TLC was checked in hexane:EtOAc (9:1). Solution was filtered and evaporated under vacuum to give a viscous liquid. Crude product was dissolved in dichloromethane (50 mL) and washed with water (2×50 mL), 5% sodium bicarbonate solution (50 mL), saturated brine (50 mL) and finally with water (2×50 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated under vacuum to give isopropyl 2-isopropoxy-6-pentadecyl-benzoate as oil (Yield: 12 g).

Example 5 Synthesis of 2-ethoxy-6-pentadecyl-benzyl alcohol

Ethyl 2-ethoxy-6-pentadecyl-benzoate (10.9 g, 27 mmol) was dissolved in dry tetrahydrofuran (60 mL). This solution was transferred to dry 250 mL three neck round bottom flask fitted with reflux condenser, mechanical stirrer and it was maintained under nitrogen atmosphere through out the reaction. To this lithium aluminum hydride (2.04 g, 54 mmol) was added slowly. Reaction was highly exothermic. After addition the solution was slowly brought to the reflux temperature and maintained at that temperature for about two hours and TLC was checked in hexane:EtOAc (8:2). After completion of reaction, excess lithium aluminum hydride was decomposed by drop-wise addition of ethylacetate (80 mL). To this 5 M HCl (100 mL) was added and organic layer was separated, dried over anhydrous sodium sulphate, concentrated under vacuum to give a light brownish solid. This was recrystallised from petroleum ether (40-60° C.) to give white solid. Yield: 8 g.

Example 6 Synthesis of 2-ethoxy-6-pentadecyl-benzaldehyde

To a 250 mL round bottom flask fitted with a reflux condenser, was added pyridinium chloro chromate (PCC) (16.1 g, 75 mmol) in anhydrous dichloromethane (100 mL). 2-Ethoxy-6-pentadecyl-benzyl alcohol (18.1 g, 50 mmol) in dichloromethane (10 mL) was added in one portion to the magnetically stirred solution. After 1.5 hr dry ether (100 mL) was added and the supernatant decanted from the black gum. The insoluble residue was washed thoroughly with diethyl ether (3×25 mL), where upon it became black granular solid. The organic solution was passed through a short pad of celite, and the solvent was removed by distillation to obtain brownish low melting solid (Yield: 15 g).

Example 7 Synthesis of diethyl 1,4-dihydro-4-(2′-ethoxy-6′-pentadecyl phenyl-2.6-dimethyl-3.5-pyridine dicarboxylate (DHP-4)

2-Ethoxy-6-pentadecyl benzaldehyde (3 g, 8.3 mmol) and ethyl acetoacetate (1.08 g, 8.3 mmol) were dissolved in n-butanol (20 mL). Acetic acid (0.5 g, 8.3 mmol) and piperidine (0.7 g, 8.3 mmol) were added and stirred at room temperature for 3-4 hrs. Ethyl-3-amino crotonate (1.08 g, 8.3 mmol) was then added and refluxed for 10 hrs. n-Butanol was evaporated and reaction mixture was washed with distilled water and extracted with dichloromethane (10 mL). Organic layer was dried over sodium sulfate, evaporated and compound was purified by column chromatography using silicagel (100-200 mesh) with hexane:EtOAc (94:6) solvent system to give diethyl 1,4-dihydro-4-(2′-ethoxy-6′-pentadecyl phenyl)-2,6-dimethyl-3,5-pyridine dicarboxylate as white powder.

Example 8 Synthesis of ethyl isopropyl 1,4-dihydro-4-(2′-ethoxy-6′-pentadecylphenyl)-2,6-dimethyl-3,5-pyridine dicarboxylate (DHP-12)

2-Ethoxy-6-pentadecyl benzaldehyde (3 g, 8.3 mmol) and isopropyl acetoacetate (1.19 g, 8.3 mmol) were dissolved in n-butanol (20 mL). Acetic acid (0.5 g, 8.3 mmol) and piperidine (0.7 g, 8.3 mmol) were added and stirred at room temperature for 3-4 hrs. Ethyl-3-amino crotonate (1.08 g, 8.3 mmol) was then added and refluxed for 10 hrs. n-Butanol was evaporated and reaction mixture was washed with distilled water and extracted with dichloromethane (10 mL). Organic layer was dried over sodium sulfate, evaporated and compound was purified by column chromatography using silica gel (100-200 mesh) with hexane:EtOAc (94:6) solvent system to give ethyl isopropyl 1,4-dihydro-4-(2′-ethoxy-6′-pentadecylphenyl)-2,6-dimethyl-3,5-pyridine dicarboxylate as viscous liquid.

Example 9 Synthesis of dimethyl 1,4-dihydro-4-(2′-isopropoxy-6′-pentadecylphenyl-2.6-dimethyl-3,5-pyridine dicarboxylate (DHP-5)

2-Isopropoxy-6-pentadecyl benzaldehyde (3.1 g, 8.3 mmol) and methyl acetoacetate (0.96 g, 8.3 mmol) were dissolved in n-butanol (20 mL). Acetic acid (0.5 g, 8.3 mmol) and piperidine (0.7 g, 8.3 mmol) were added and stirred at room temperature for 3-4 hrs. methyl-3-amino crotonate (0.97 g, 8.3 mmol) was then added and refluxed for 10 hrs. n-Butanol was evaporated and reaction mixture was washed with distilled water and extracted with dichloromethane (10 mL). Organic layer was dried over sodium sulfate, evaporated and compound was purified by column chromatography using silicagel (100-200 mesh) with hexane:EtOAc (94:6) solvent system to give dimethyl 1,4-dihydro-4-(2′-isopropoxy-6′-pentadecylphenyl)-2,6-dimethyl-3,5-pyridine dicarboxylate as viscous liquid.

Example 10 Synthesis of diethyl 1,4-dihydro-4-(2′-ethoxy-6′-pentadecyl phenyl)-6-methyl-2-(2′-mercapto-1′H-benzimidazolyl)methyl-3,5-pyridine dicarboxylate (DHP-27)

2-Ethoxy-6-pentadecylbenzaldehyde (3 g, 8.3 mmol) and 4-chloro ethyl acetoacetate (1.36 g, 8.3 mmol) were dissolved in n-butanol (20 mL). Acetic acid (0.5 g, 8.3 mmol) and piperidine (0.7 g, 8.3 mmol) were added and stirred at room temperature for 3-4 hrs. Ethyl-3-amino crotonate (1.08 g, 8.3 mmol) was then added and refluxed for 10 hrs. n-Butanol was evaporated and reaction mixture was washed with distilled water and extracted with dichloromethane (10 mL). Organic layer was dried over sodium sulfate, evaporated and compound was purified by column chromatography using silicagel (100-200 mesh) with hexane:EtOAc (94:6) solvent system to give diethyl 1,4-dihydro-4-(2′-ethoxy-6′-pentadecylphenyl)-6-methyl-2-chloromethyl-3,5-pyridine dicarboxylate. This compound (0.6 g, 1.2 mmol)was dissolved in dichloromethane (10 mL) and then 2-mercapto-1H-benzimidazole (0.18 g, 1.2 mmol) and NaOH (0.048 g, 1.2 mmol) were charged. Catalytic amount of tetrabutyl ammonium bromide was added and magnetically stirred at room temperature for 2 hrs. The final compound was purified by column chromatography as mentioned in Example 7.

Example 11 Synthesis of ethyl 2-methoxyethyl 1,4-dihydro-4-(2′-ethoxy-6′-pentadecylphenyl)-2,6-dimethyl-3,5 pyridine dicarboxylate (DHP-653)

2-Ethoxy-6-pentadecyl benzaldehyde (3 g, 8.3 mmol) and methoxy ethyl acetoacetate (1.32 g, 8.3 mmol) were dissolved in n-butanol (20 mL). Acetic acid (0.5 g, 8.3 mmol) and piperidine (0.7 g, 8.3 mmol) were added and stirred at room temperature for 3-4 hrs. Ethyl-3-amino crotonate (1.08 g, 8.3 mmol) was then added and refluxed for 10 hrs. n-Butanol was evaporated and reaction mixture was washed with distilled water and extracted with dichloromethane (10 mL). Organic layer was dried over sodium sulfate, evaporated and compound was purified by column chromatography using silicagel (100-200 mesh) with hexane:EtOAc (94:6) solvent system to give ethyl 2-methoxyethyl,4-dihydro-4-(2′-ethoxy-6′-pentadecylphenyl)-2,6-dimethyl-3,5 pyridine dicarboxylate.

Example 12 Synthesis of diethyl 1,4-dihydro-4-(2′-(2″methoxy) ethoxy-6′-pentadecylphenyl)-2,6-dimethyl-3,5-pyridine dicarboxylate (DHP-654)

2-(2′-methoxyethoxy)-6-pentadecyl benzaldehyde (3.2 g, 8.3 mmol) and ethyl acetoacetate (1.08 g, 8.3 mmol) were dissolved in n-butanol (20 mL). Acetic acid (0.5 g, 8.3 mmol) and piperidine (0.7 g, 8.3 mmol) were added and stirred at room temperature for 3-4 hrs. Ethyl-3-amino crotonate (1.08 g, 8.3 mmol) was then added and refluxed for 10 hrs. n-Butanol was evaporated and reaction mixture was washed with distilled water and extracted with dichloromethane (10 mL). Organic layer was dried over sodium sulfate, evaporated and compound was purified by column chromatography using silicagel (100-200 mesh) with hexane:EtOAc (94:6) solvent system to give-diethyl 1,4-dihydro-4-(2′-(2″methoxy)ethoxy-6′-pentadecylphenyl)-2,6-dimethyl-3,5-pyridine dicarboxylate.

Example 13 Synthesis of diethyl 1,4-dihydro-4-(2′-ethoxy-6′-pentadecylphenyl)-2-((2′-amino ethoxy)methyl)-6-methyl-3.5-pyridine dicarboxylate (DHP-84)

2-Ethoxy-6-pentadecyl benzaldehyde (3 g, 8.3 mmol) and 4-chloro ethyl acetoacetate (1.36 g, 8.3 mmol) were dissolved in n-butanol (20 mL). Acetic acid (0.5 g, 8.3 mmol) and piperidine (0.7 g, 8.3 mmol) were added and stirred at room temperature for 3-4 hrs. Ethyl-3-amino crotonate (1.08 g, 8.3 mmol) was then added and refluxed for 10 hrs. n-Butanol was evaporated and reaction mixture was washed with distilled water and extracted with dichloromethane (10 mL). Organic layer was dried over sodium sulfate, evaporated and compound was purified by column chromatography using silicagel (100-200 mesh) with hexane:EtOAc (94:6) solvent system to give diethyl 1,4-dihydro-4-(2′-ethoxy-6′-pentadecylphenyl)-2-chloromethyl-6-methyl-3,5-pyridine dicarboxylate). This compound (0.6. g, 1 mmol )was dissolved in dichloromethane (10 mL) and 2-amino ethanol (0.061 g, 1 mmol) and KOH (0.06 g, 1 mmol) were added and stirred magnetically for 15 min. Then catalytic amount of dibenzo-18-crown-6 and tetrabutyl ammonium bromide was added and stirred for one hour. Then the product was purified by column chromatography as mentioned in example 7.

Example 14 Synthesis of diethyl 1,4-dihydro-4-(2′-ethoxy-3′,5′-dinitro-6′-pentadecylphenyl)-2,6-dimethyl-3,5-pyridine dicarboxylate (DHP-132)

2-Ethoxy-3,5-dinitro-6-pentadecyl benzaldehyde (3.73 g, 8.3 mmol) and ethyl acetoacetate (1.08 g, 8.3 mmol) were dissolved in n-butanol (20 mL). Acetic acid (0.5 g, 8.3 mmol) and piperidine (0.7 g, 8.3 mmol) were added and stirred at room temperature for 3-4 hrs. Ethyl-3-amino crotonate (1.08 g, 8.3 mmol) was then added and refluxed for 10 hrs. n-Butanol was evaporated and reaction mixture was washed with distilled water and extracted with dichloromethane (10 mL). Organic layer was dried over sodium sulfate, evaporated and compound was purified by column chromatography using silicagel (100-200 mesh) with hexane:EtOAc (94:6) solvent system to give diethyl 1,4-dihydro-4-(2′-ethoxy-3′,5′-dinitro-6′-pentadecylphenyl)-2,6-dimethyl-3,5-pyridine dicarboxylate.

Example 15 Synthesis of diethyl 1,4-dihydro-4-(2′-ethoxy-3′-amino-6′-pentadecylphenyl)-2,6-dimethyl-3,5-pyridine dicarboxylate (DHP-655)

2-Ethoxy-3-acetanilido-6-pentadecyl benzaldehyde (3.46 g, 8.3 mmol) and ethyl acetoacetate (1.08 g, 8.3 mmol) were dissolved in n-butanol (20 mL). Acetic acid (0.5 g, 8.3 mmol) and piperidine (0.7 g, 8.3 mmol) were added and stirred at room temperature for 3-4 hrs. Ethyl-3-amino crotonate (1.08g, 8.3 mmol) was then added and refluxed for 10 hrs. n-Butanol was evaporated and reaction mixture was washed with distilled water and extracted with dichloromethane (10 mL). Organic layer was dried over sodium sulfate, evaporated and compound was hydrolised and purified by column chromatography using silicagel (100-200 mesh) with hexane:EtOAc (94:6) solvent system to give diethyl 1,4-dihydro-4-(2′-ethoxy-3′-amino-6′-pentadecylphenyl)-2,6-dimethyl-3,5-pyridine.

Example 16 Synthesis of diethyl 1,4-dihydro-4-(2′-ethoxy-6′-pentadecyl phenyl)-6-methyl-2-(5″-methyl-2′-mercapto-1′H-benzimidazolyl)methyl-3,5-pyridine dicarboxylate (DHP-276)

2-Ethoxy-6-pentadecyl benzaldehyde (3 g, 8.3 mmol) and 4-chloro ethyl acetoacetate (1.36 g, 8.3 mmol) were dissolved in n-butanol (20 mL). Acetic acid (0.5 g, 8.3 mmol) and piperidine (0.7 g, 8.3 mmol) were added and stirred at room temperature for 3-4 hrs. Ethyl-3-amino crotonate (1.08 g, 8.3 mmol) was then added and refluxed for 10 hrs. n-Butanol was evaporated and reaction mixture was washed with distilled water and extracted with dichloromethane (10 mL). Organic layer was dried over sodium sulfate, evaporated and compound was purified by column chromatography using silicagel (100-200 mesh) with hexane:EtOAc (94:6) solvent system to give diethyl 1,4-dihydro-4-(2′-ethoxy-6′-pentadecylphenyl)-6-methyl-2-chloromethyl-3,5-pyridine dicarboxylate. This compound (0.6 g, 1 mmol) was dissolved in dichloromethane (10 mL) and then (5′-methyl) 2-mercapto-1H-bezimidazole (0.164 g, 1 mmol) and NaOH (0.04 g, 1 mmol) were charged. Catalytic amount of tetrabutyl ammonium bromide and dibenzo-18-crown-6 were added and magnetically stirred at room temperature for 2 hrs. The final compound was purified by column chromatography as mentioned in Example 7.

Example 17 Aromatization of Hantzsch 1,4-dihydropyridines with FeCl₃/Acetic acid

Any of the 1,4-dihydropyridine compounds of the present invention can be converted to the corresponding pyridine compound, as shown in Scheme 13, using the following procedure: A mixture of Hantzsch 1,4-dihydropyridine (10 mmol) and ferric chloride (21 mmol) in acetic acid (30 mL) at room temperature was stirred for an appropriate period (20 minutes to 2 hours). Progress of the reaction was monitored by TLC, and after completion, the reaction was quenched, by pouring it in water (300 mL). The precipitated oil was extracted with ethyl acetate (3×50 mL). Organic layer was separated and was neutralized with NaHCO₃ solution (2 M, 2×100 mL) and washed with saturated brine solution (100 mL) and then with distilled water (100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to yield pyridine analogue. The resulting crude product was purified by silicagel column chromatography (100-200 mesh, EtOAc/Hexane, 7:3) to afford the corresponding pyridine.

Example 18 Expression of T-type Channels in Mammalian Cells

T-type calcium channels (α1G) were stably expressed in HEK₂₉₃ cells and maintained at 37° C. in DMEM. Cells were released from dishes using trypsin and EGTA or Accutase and studied within 4 hours of isolation. Individual cells were placed on the stage of an inverted microscope and patched with pipettes pulled from aluminasilicate glass capillary tubes, which had resistances of 0.8-1.5 Mohm. Currents were recorded using an Axopatch 200 (Axon Instruments, Inc.) and pClamp data acquisition software (8.1). The pipette solution contained (in mM): KCl 130, EGTA 11, HEPES 10, MGATP 5, pH ═7.4. The bath solution contained (in mM): NaCl 140, CaCl₂ 1, HEPES 10, pH═7.4. Test compounds were diluted into bath solution to the desired concentration (100 nM-10 μM) from a stock solutions (3 or 10 mM in DMSO). Current measurements were made at 20-23° C. Cells were held at −110 mV in order to maximize occupancy in the closed state and depolarized for 100 ms to various potentials. Currents were capacity corrected using 16-64 subthreshold responses (voltage steps of 10 or 20 mV) and leak subtracted, based on linear interpolation between the current at the holding potential and 0 mV. Cells were moved from a control chamber to a chamber with test compound and the effect of the drug was assessed using a voltage clamp protocol that stepped to −30 mV for 100 ms from a holding potential of −110 mV once every 5 s. After each 10-13 minutes, the train protocol was interrupted and a full current voltage relationship obtained. In general for each compound, four cells were studied for a minimum of 13 minutes, two in drug at 500 nM and two at 1 μM. In some cases other concentrations were also studied. Data were analyzed using Matlab (Mathworks, Natick, Mass.). Drug efficacy was estimated using the relationship: Blocked Fraction=[Drug]/(IC ₅₀+[Drug])

The results are set forth in the table below:

% of calcium channels blocked Compound 500 nM of 1 μM of No. comp'd comp'd DHP-5 80 DHP-12 5 77 DHP-338 30 95 DHP-331 80 Mibefradil 75 90 Nifedipine 0 15

REFERENCES

Methods of Testing for Pharmacological Activities of the Compounds:

1. Against calcium T-type channels (low voltage activated calcium channels):

-   -   a) L. Lacinova, N. Klugbauer, F. Hofmann “Regulation of the         calcium channel α_(1G) subunit by divalent cations and organic         blockers” Neuropharmacology, 39, 1254-1266 (2000).     -   b) J. P. Clozel, E. A. Ertel, S. I. Ertel “Discovery and main         pharmacological properties of mibefradil (Ro 40-5967), the first         selective T-type calcium channel blocker” Journal of         hypertension 15, S17-S25 (1997).     -   c) G. Mehrke, X. G. Zong, V. Flockerzi, F. Hofmann “The Ca²⁺         channel blocker Ro 40-5967 blocks differently T-type and L-type         Ca²⁺ channels” Journal of Pharmacology and Experimental         Therapeutics, 271, 1483-1488 (1994).     -   d) S. Richard, S. Diochot, J. Nargeot, M. Baldy-Moulinier, J.         Valmier “Inhibition of T-type calcium currents by         dihydropyridines in mouse embryonic dorsal root ganglion         neurons” Neuroscience Letters 132, 229-234 (1991).     -   e) R. S. I. Chaung, H. Jaffe, L. Cribbs, E. Perez-Reyes, K. J.         Swartz “Inhibition of T-type voltage gated calcium channel by a         new scorpion toxin” Nature Neuroscience, 1, 668-674 (1998).         2. Against calcium L-type channels (high voltage activated         calcium channels):     -   a) B. Z. Peterson, C. D. DeMaria, D. T. Yue “Calmodulin is the         Ca²⁺ sensor for Ca²⁺-dependent inactivation of L-type calcium         channels” Neuron, 22, 549-558 (1999).     -   b) G. C. Rovnyak, S. D. Kimball, B. Beyer, G. Cucinotta, J. D.         DiMarco, J. Gougoutas, A. Hedberg, M. Malley, J. P. McCarthy, R.         Zhang, S. Moreland “Calcium Entry Blockers and Activators:         Conformational and Structural Determinants of Dihydropyrimidine         Calcium Channel Modulators” Journal of Medicinal Chemistry, 38,         199-129 (1995).         3. Against N-, P/Q-, and R- types of calcium channels:     -   a) Stea, A.; Soong, T. W.; Snutch, T. P. “Voltage gated calcium         channels,” in Handbook of Receptors and Channels; Ligand-and         Voltage-Gated Ion Channels (North RA ed.), 1995, 113-152, CRC         Press Inc., Boca Raton, Fla.     -   b) Zamponi, G. W. “Antagonist sites of voltage dependent calcium         channels,” Drug Development Research, 1997, 42, 131-143.     -   c) Neelands, T. R.; King, A. P.; Macdonald, R. L. “Functional         expression of L-, N-, P/Q-, and R-type calcium channels in the         human NT2-N cell line,” J. Neurophysiol. 2000, 84(6), 393-401.         4. References on 1,4-dihydropyridines:     -   a) Goldmann, S.; Stoltefuss, J. Angew. Chem. Int. Ed. Engl.         1991, 30, 1559.     -   b) Loev, B.; Goodman, M. M.; Snader, K. M.; Tedeschi, R.;         Macko, E. J. Med. Chem. 1974,17, 956.

CONCLUSION

Thus, those of skill in the art will appreciate that the compounds and uses disclosed herein can be used as calcium channel blockers, providing a therapeutic effect.

One skilled in the art will appreciate that these methods and compounds are and may be adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those inherent therein. The methods, procedures, and compounds described herein are presently representative of preferred embodiments and are exemplary and are not intended as limitations on the scope of the invention. Changes therein and other uses will occur to those skilled in the art which are encompassed within the spirit of the invention and are defined by the scope of the claims.

It will be apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention.

Those skilled in the art recognize that the aspects and embodiments of the invention set forth herein may be practiced separate from each other or in conjunction with each other. Therefore, combinations of separate embodiments are within the scope of the invention as claimed herein.

All patents and publications mentioned in the specification are indicative of the levels of those skilled in the art to which the invention pertains. All patents and publications are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.

The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein. Thus, for example, in each instance herein any of the terms “comprising”, “consisting essentially of” and “consisting of” may be replaced with either of the other two terms. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions indicates the exclusion of equivalents of the features shown and described or portions thereof. It is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims.

In addition, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group. For example, if X is described as selected from the group consisting of bromine, chlorine, and iodine, claims for X being bromine and claims for X being bromine and chlorine are fully described.

Other embodiments are within the following claims. 

1. A compound of Formula I or II

or a pharmaceutically acceptable salt, amide, ester, or prodrug thereof, where a) R₁ is an straight-chain, branched, or cyclic alkyl group having greater than eight carbon atoms; b) R₂-R₉ are each independently selected from the group consisting of hydrogen, halogen, perhaloalkyl, nitro, amino, a diazo salt, optionally substituted lower alkyl, optionally substituted lower alkylene, optionally substituted lower alkoxy, optionally substituted lower alkoxyalkyl, optionally substituted lower alkoxyalkoxy, optionally substituted lower mercaptyl, optionally substituted lower mercaptoalkyl, optionally substituted lower mercaptomercaptyl, —C(O)OH, —OC(O)H, —C(O)OR, —OC(O)R, —C(S)OR, —OC(S)R, —C(O)SR, —SC(O)R, —C(S)SR, —SC(S)R, C-amido, N-amido, and optionally substituted five- or six-membered heteroaryl ring or optionally substituted six-membered aryl or heteroaryl ring, where the lower alkyl and the lower alkylene moieties are each independently and optionally substituted with one or more substituents selected from the group consisting of halogen, perhaloalkyl, nitro, amino, hydroxy, alkoxy, sulfhydryl, thioether, cyano, amido, ester, and

where A is selected from the group consisting of oxygen, sulfur, and —NH and R₁₂ is selected for the group consisting of hydrogen, hydroxy, alkoxy, haloalkoxy, halogen, haloalkyl, perhaloalkyl, nitro, amino, and a diazo salt, and n is between 0-4; and where the ring moieties are each independently and optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkylene, c) R₁₀ and R₁₁ in the compound of Formula I are each independently selected from the group consisting of hydrogen and lower alkyl; provided that: when R₁ is C₁₅H₃₁, R₂ and R₃ are both CH₃, R₄ is C(O)OCH(CH₃)₂, and R₆ is either OCH₃, OCH₂CH₃, or OCH(CH₃)₂, then R₅ is not C(O)OCH₃, C(O)OCH₂CH₃, or C(O)OCH(CH₃)₂; or when R₁ is C₁₅H₃₁, R₃ and R₃ are both CH₃, R₄ is C(O)OCH₂CH₃, and R₆ is either OCH₃ or OCH₂CH₃, then R₅ is not C(O)OCH₃ or C(O)OCH₂CH₃; or when R₁ is C₁₅H₃₁, R₂ and R₃ are both CH₃, R₆ is OCH(CH₃)₂, and R₄ is either C(O)OCH₃ or C(O)OCH₂CH₃, then R₅ is not C(O)OCH₃ or C(O)OCH₂ch₃.
 2. The compound of claim 1, wherein R₁ has greater than or equal to fifteen carbon atoms.
 3. The compound of claim 1, wherein R₁ is an optionally substituted C₁₅ straight-chain alkyl group.
 4. The compound of claim 1, wherein R₂ and R₃ are each independently an optionally substituted alkyl group.
 5. The compound of claim 4, wherein R₂ and R₃ are each independently selected from the group consisting of methyl, ethyl, or isopropyl.
 6. The compound of claim 1, wherein R₄ is

wherein A is selected from the group consisting of oxygen, sulfur, and —NH; R₁₂ is selected from the group consisting of hydrogen, hydroxy, alkoxy, haloalkoxy, halogen, haloalkyl, perhaloalkyl, nitro, amino, and a diazo salt, and n is between 0-4.
 7. The compound of claim 1, wherein R₄ and R₅ are each independently selected from the group consisting of a) an optionally substituted alkyl group; b) an alkoxy of formula —(X₁)_(n1)—O—X₂, where X₁ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl, and heteroaryl; X₂ is selected from the group consisting of hydrogen, lower alkyl, aryl, and heteroaryl; and n1 is 0 or 1; and c) a thioether or thiol of formula —(X₃)_(n3)—S—X₄, where X₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl, and heteroaryl; X₄ is selected from the group consisting of hydrogen, lower alkyl, aryl, and heteroaryl; and n3 is 0 or 1; d) a carboxylic acid of formula —(X₅)_(n5)—C(═E)—E′H, where X₅ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl, and heteroaryl; E and E′ are each independently selected from the group consisting of oxygen and sulfur; n5 is 0 or 1; and e) an ester of formula —(X₆)_(n6)—C(═E)—E′X₇, or of formula —(X₆)_(n6)—E′—C(═E)—X₇, where X₆ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl, and heteroaryl; E and E′ are each independently selected from the group consisting of oxygen and sulfur; X₇ is selected from the group consisting of hydrogen lower alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino, and —NX₈X₉, where X₈ and X₉ are each independently selected from the group consisting of hydrogen, alkyl, aryl, and heteroaryl; and n6 is 0 or
 1. 8. The compound of claim 7, wherein R₄ and R₅ are selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl.
 9. The compound of claim 7, wherein n1, n3, n5, and n6 are each independently 1, and X_(1, X) ₃, X₅, and X₆ are each independently methylene.
 10. The compound of claim 7, wherein X_(2, X) ₄, and X₇ are each independently selected from the group consisting of methyl, ethyl, and isopropyl.
 11. The compound of claim 7, wherein E and E′ are each independently oxygen.
 12. The compound of claim 7, wherein E is sulfur and E′, if it exists, is oxygen.
 13. The compound of claim 7, wherein R₄ and R₅ are each independently selected from the group consisting of —C(O)OH, —C(O)OCH₃, —C(O)OCH₂CH₃, —C(O)OCH(CH₃)₂, —CH₂OCH₃, —CH₂OCH₂CH₃, and —CH₂OCH(CH₃)₂.
 14. The compound of claim 1, wherein R₆ is selected from the group consisting of a) hydrogen; b) an optionally substituted alkyl group; c) an alkoxy of formula —(X₁)_(n1)—O—X₂, where X₁ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl, and heteroaryl; X₂ is selected from the group consisting of hydrogen, lower alkyl, aryl, and heteroaryl; and n1 is 0 or 1; and d) a thioether or thiol of formula —(X₃)_(n3)—S—X₄, where X₃ is selected from to group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl, and heteroaryl; X₄ is selected from the group consisting of hydrogen, lower alkyl, aryl, and heteroaryl; and n3 is 0 or 1; e) a carboxylic acid of formula —(X₅)_(n5)—C(═E)—E′H, where X₅ is selected from to group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl, and heteroaryl; E and E′ are each independently selected from the group consisting of oxygen and sulfur; n5 is 0 or 1; and f) an ester of formula —(X₆)_(n6)—C(═E)—E′X₇, or of formula —(X₆)_(n6)—E′—C(═E)—X₇, where X₆ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl, and heteroaryl; E and E′ are each independently selected from the group consisting of oxygen and sulfur; X₇ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino, and —NX₈X₉, where X₈ and X₉ are each independently selected from the group consisting of hydrogen, alkyl, aryl, and heteroaryl; and n6 is 0 or
 1. 15. The compound of claim 14, wherein said alkyl is a lower alkyl, selected from the group consisting of methyl, ethyl, and isopropyl.
 16. The compound of claim 14, wherein R₆ is an alkoxy selected from the group consisting of methoxy, ethoxy, and isopropoxy.
 17. The compound of claim 1, wherein R₇-R₉ are each independently selected from the group consisting of a) hydrogen; b) an optionally substituted alkyl group; c) an alkoxy of formula —(X₁)_(n1)—O—X₂, where X₁ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl, and heteroaryl; X₂ is selected from the group consisting of hydrogen, lower alkyl, aryl, and heteroaryl; and n1 is 0 or 1; and d) a thioether or thiol of formula —(X₃)_(n3)—S—X₄, where X₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl, and heteroaryl; X₄ is selected from the group consisting of hydrogen, lower alkyl, aryl, and heteroaryl; and n3 is 0 or 1; e) a carboxylic acid of formula —(X₅)_(n5)—C(═E)—E′H, where X₅ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl, and heteroaryl; E and E′ are each independently selected from the group consisting of oxygen and sulfur; n5 is 0 or 1; f) an ester of formula —(X₆)_(n6)—C(═E)—E′X₇, or of formula —(X₆)_(n6)—E′—C(═E)—X₇, where X₆ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl, and heteroaryl; E and E′ are each independently selected from the group consisting of oxygen and sulfur; X₇ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino, and —NX₈X₉, where X₈ and X₉ are each independently selected from the group consisting of hydrogen, alkyl, aryl, and heteroaryl; and n6 is 0 or 1; g) an amine of formula —(X₁₀)_(n10)—NX₁₁X₁₂, where X₁₀ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl, and heteroaryl; where X₁₀ and X₁₁ are each independently selected from the group consisting of hydrogen, alkyl, aryl, and heteroaryl; and n10 is 0 or 1; h) NO₂; and i) halogen or perhaloalkyl.
 18. The compound of claim 17, wherein R₇-R₉ are each independently selected from the group consisting of hydrogen, hydroxy, nitro (NO₂), amino (NH₂), methyl, ethyl, isopropyl, fluoro, and chloro.
 19. The compound of claim 1, wherein R₁₀ and R₁₁ are each hydrogen. 